PUBCHEM.COMPOUND:3345

The study developed chimeric monoclonal antibodies (mAb) that can specifically bind with fentanyl and its analogs in the periphery, preventing them from reaching the central nervous system. This mAb-based passive immunotherapy does not interfere with other medications used to treat opioid use disorder (OUD). The study found that two mAb candidates with high binding affinities to fentanyl and its analogs were effective in engaging fentanyl in the periphery and blocking its effects in animals.


PUBCHEM.COMPOUND:23582940

The study presents the design and synthesis of four haptens (1-AmidoMorHap, 1-AmidoMorHap epimer, 1 Amido-DihydroMorHap, and 1 Amido-DihydroMorHap epimer) as potential medications for opioid use disorder. These haptens are hydrolytically stable surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. The haptens were conjugated with tetanus toxoid (TT) and tested for their efficacy in vivo. The results showed that all TT-hapten conjugates induced high antibody endpoint titers against the targets, but only haptens 2 and 3 induced protective effects against heroin in vivo. The study also found that the chirality at C6 in these epoxymorphinans is crucial to their effectiveness.


PUBCHEM.COMPOUND:155906823


EFO:0009510

The study investigates the impact of peripheral nerve injury on neuropathic pain and sympathetic activity in two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG). The results showed that both models led to neuroinflammatory changes in the sympathetic ganglia, characterized by macrophage responses, satellite glia activation, and increased numbers of T cells. There were also slight increases in sympathetic neuron excitability. The spinal nerve ligation model generally caused larger responses than DRG inflammation.


EFO:0009510


UBERON:0009623


GO:1990791


PR:000004141

The study found that Apolipoprotein A-I binding protein (AIBP) can prevent and reverse processes associated with neuroinflammatory-mediated spinal nociceptive processing. This is achieved through AIBP binding to Toll-like receptor-4 (TLR4) and increased binding of AIBP to activated microglia, which mediates selective regulation of lipid rafts in inflammatory cells. AIBP-mediated lipid raft reductions downregulate LPS-induced TLR4 dimerization, inflammatory signaling, and expression of cytokines in microglia. In mice, intrathecal injections of AIBP reduce spinal myeloid cell lipid rafts, TLR4 dimerization, neuroinflammation, and glial activation. AIBP also reverses established allodynia in mice in which pain states were induced by the chemotherapeutic cisplatin, intraplantar formalin, or intrathecal LPS, all of which are pro-nociceptive interventions known to be regulated by TLR4 signaling.


PR:000004141


MONDO:0043797

The study investigates the role of immune responses in the development of neuropathic pain following spinal cord injury (SCI) and the potential of exercise in modulating these responses. The researchers found that rats with SCI-induced pain had greater microglial activation in the C7-C8 dorsal horn and an increased number of macrophages in the dorsal root ganglia (DRG). Early exercise post-SCI was found to reduce microglial activation and the number of macrophages in the DRG, suggesting that exercise may prevent pain by modulating the injury-induced macrophage response in the DRG.


MONDO:0043797


HP:0410139


MESH:C478941

The study investigates the role of sex in central neuropathic pain and its pharmacological inhibition in individuals with spinal cord injury (SCI). The analgesic efficacy of pioglitazone (PIO), a drug approved for diabetes treatment, and azithromycin (AZM), a commonly prescribed antibiotic with immunomodulatory properties, was tested in a mouse model of SCI pain. The results showed a sex-specific effect of PIO with significant antihyperalgesic effects in females, but not males. However, AZM was effective in both sexes. The findings support the use of PIO and AZM as novel therapies for SCI pain and emphasize the importance of considering sex as a biological variable in clinical and experimental SCI pain research.


CHEMBL.COMPOUND:CHEMBL3545150

has antihyperalgesic effects in both sexes


MESH:C478941


CHEMBL.COMPOUND:CHEMBL3545150

is a potential treatment for pain associated with


PUBCHEM.COMPOUND:6604954

The study investigates the role of calcium permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in chronic pain. The researchers found that acute inflammation triggers the accumulation of CP-AMPARs in the dorsal horn of the spinal cord, which contributes to acute inflammatory pain. The study also found that the CP-AMPAR antagonist IEM-1460 inhibited AMPAR-evoked Ca2+ transients after injury. The study concludes that CP-AMPAR inhibitors could be a promising class of agents for the treatment of chronic inflammatory pain.


PUBCHEM.COMPOUND:141698393


PUBCHEM.COMPOUND:23376553

The study investigates the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), in comparison with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons. All three agonists inhibited PGE2-stimulated cAMP accumulation and activated ERK with similar efficacy. However, ERK activation by U50488 was Gi-protein mediated, while that by DPDPE or 6'-GNTI was Gi-protein independent. In vivo, all three agonists reduced thermal nociception. The study suggests that DOP-KOP heteromers exhibit unique signaling and functional regulation in peripheral sensory neurons and may be a promising therapeutic target for the treatment of pain.


UniProtKB:A0A6L6Y1H2


PUBCHEM.COMPOUND:13786989

12- and 15- hydroxyeicosatetraenoic acid


MESH:C021578

The study investigates the role of Methylglyoxal (MG) in Painful Diabetic Neuropathy (PDN) in type 2 diabetes using db/db mice and C57BL/6J mice. The study found that administration of a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the enzyme that breaks down MG, reduced heat hypersensitivity in db/db mice. In C57BL/6J mice, MG administration resulted in signs of pain. The study concludes that MG and a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice, suggesting potential treatments for PDN in type 2 diabetes.


UniProtKB:A0A8C7WRF4


UniProtKB:A0A6J8ELD2


UniProtKB:A0A2D1P855


UniProtKB:W5JB50


PR:000030577

The study reveals the significant role of apolipoprotein A-I binding protein (AIBP) in regulating cholesterol efflux and lipid rafts, which are cholesterol-rich and sphingomyelin-rich membrane domains. AIBP mediates selective cholesterol efflux, particularly through binding to toll-like receptor-4 (TLR4) in activated macrophages and microglia, thereby reversing lipid raft increases in activated cells. AIBP also regulates the function of vascular endothelial growth factor receptor-2, Notch1, and TLR4. In animal models, AIBP deficiency leads to accelerated angiogenesis, increased inflammation, and exacerbated atherosclerosis. The administration of recombinant AIBP reduces inflammation and persistent pain in a mouse model of chemotherapy-induced polyneuropathy and reduces lipopolysaccharide-induced acute lung injury. These findings suggest potential therapeutic applications for AIBP in angiogenic and inflammatory diseases.


PR:000030577


PR:000030577

Vascular endothelial growth factor receptor-2


PR:000030577

Lipopolysaccharide-induced acute lung injury


UniProtKB:A0A6G1R1G5

The study investigates the role of TWIK-related spinal cord K+ (TRESK) channel in trigeminal pain processing. The research used TRESK global knock-out mice as a model system and found that the loss of TRESK increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4-). This resulted in hyper-excitation of the small IB4- dural afferent neurons. Both male and female TRESK knock-out mice exhibited more robust trigeminal nociceptive behaviors, including headache-related behaviors. The study concludes that endogenous TRESK activity regulates trigeminal nociception, likely through controlling the intrinsic excitability of TG nociceptors, and that genetic loss of TRESK significantly increases the likelihood of developing a headache.


UniProtKB:A0A6G1R1G5


MESH:D063388

The paper discusses the role of endocannabinoids, a type of neurotransmitter system, in providing short-term pain relief following spinal manipulative therapy, a treatment used for chronic pain. The research suggests that endocannabinoids contribute to the analgesic effect of this therapy, and understanding their involvement could improve the clinical efficacy of the treatment.


CHEBI:50824

The study presents a pH-responsive, soft polymeric nanoparticle designed to target acidified endosomes and inhibit endosomal signalling events that lead to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) moves from the plasma membrane to acidified endosomes, where it signals to maintain pain. The nanoparticles enter cells via clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. When injected into rodents, the nanoparticles, which contain the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. This treatment results in complete and persistent relief from nociceptive, inflammatory, and neuropathic nociception, providing a non-opioid treatment option for chronic pain.


NCBIGene:6869

Substance P (SP) neurokinin 1 receptor (NK1R)


NCBIGene:6869


CHEBI:50824


PUBCHEM.COMPOUND:135413536


CHEBI:50824

Nociceptive, inflammatory, and neuropathic nociception


NCBIGene:234219

Central nucleus of the amygdala (GABACeA)

The study identifies a neural pathway that may be responsible for comorbid pain in depression (CP). This pathway involves GABAergic neurons from the central nucleus of the amygdala (GABACeA) projecting to glutamatergic neurons in the parafascicular nucleus (GluPF), which then relay directly to neurons in the second somatosensory cortex (S2). Enhanced inhibition of this pathway is found in mice exhibiting CP symptoms. Using chemogenetic or optogenetic approaches to reverse this pathway alleviates CP symptoms.


GO:0035249


NCBIGene:234219


UniProtKB:A0A653V407

The paper discusses the role of lipid rafts in glial cells and their contribution to neuroinflammatory sensitization of central pain signaling pathways. The authors introduce the concept of an "inflammaraft" (i-raft), which are enlarged lipid rafts that contain activated receptors and adaptor molecules, initiating inflammatory signaling and cellular response. The study highlights the involvement of inflammatory receptors, redox molecules, and ion channels in inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in inflammaraft maintenance and disruption. The paper suggests that targeting inflammarafts could lead to new therapies for neuropathic pain states and other neuroinflammatory conditions.


GO:0001765


PUBCHEM.COMPOUND:5997


CHEBI:26739


MONDO:0004466


PR:000001155


EFO:0003843

The study found that short-term pain, induced by an injection of complete Freund's adjuvant (CFA), decreased voluntary morphine intake in rats. This decrease was blocked by pre-treatment with indomethacin, a non-opioid inhibitor of pain. In rats with steady morphine self-administration, the protein level of GluA1 subunits of glutamate AMPA receptors was increased in the central nucleus of the amygdala (CeA), while that of GluA2 was decreased. This resulted in an increased GluA1/GluA2 ratio. Pain decreased this ratio. Microinjection of NASPM, an inhibitor of GluA1-AMPARs, into CeA inhibited morphine intake. Overexpression of GluA1 protein in CeA maintained morphine intake at a higher level and reversed the pain-induced reduction in morphine intake. This suggests that CeA GluA1 promotes opioid use and its upregulation increases opioid consumption, counteracting the acute inhibitory effect of pain on opioid intake.


PUBCHEM.COMPOUND:3715


UniProtKB:A0A5A4LKE5


UniProtKB:A0A5A4M1S9


PUBCHEM.COMPOUND:16219727


NCBIGene:4897

The study investigates the role of alternative splicing of the Nrcam gene in neuropathic pain. Two splicing variants of Nrcam, Nrcam+10 and Nrcam-10, were found to be differentially expressed in the dorsal root ganglions (DRGs) after spinal nerve ligation (SNL) in mice. SNL increased the amount of Nrcam+10 and decreased the level of Nrcam-10. An antisense oligonucleotide (ASO) targeting exon 10 of Nrcam gene repressed Nrcam+10 expression and increased Nrcam-10 expression in DRG cell culture. Injections of Nrcam ASO attenuated SNL-induced pain hypersensitivities. The study concludes that the relative levels of alternatively spliced Nrcam variants are critical for neuropathic pain genesis.


NCBIGene:4897


MESH:C558606


NCBIGene:460993

expression increased following nerve injury

The study found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Inhibition of GPR160 in the spinal cord prevented and reversed neuropathic pain in rodents without altering normal pain response. The study also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in the spinal cord attenuated neuropathic pain, while exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB).


PR:000004969

The study discusses the role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pathophysiology. It highlights the development and clinical testing of drugs targeting CGRP or its receptor, which have been found to alleviate migraine symptoms in half of the patients. The study also suggests that a second CGRP receptor could be a new therapeutic target. The CGRP-targeting drugs have shown a remarkable safety profile, which may be due to the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity.


GTOPDB:681


UniProtKB:A0A9L0SH84


NCBIGene:34708

The study identifies the histone deacetylase Sirtuin 1 (SIRT1) in the central amygdala as a key regulator in controlling the development of comorbid emotional disorders, which underlie individual vulnerability to chronic pain. The study found that animals vulnerable to developing behaviors of anxiety and depression under pain conditions displayed reduced SIRT1 protein levels in the central amygdala. Overexpression of local SIRT1 reversed this vulnerability, while knockdown of local SIRT1 mimicked the pain effect. The action of SIRT1 was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at the CaMKIIα promoter. The study suggests that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders.


NCBIGene:34708


UniProtKB:Q7TUX1

The paper discusses the role of cytokines, a type of soluble mediator, in the development and maintenance of inflammatory and neuropathic pain. The study suggests that cytokines facilitate nociceptive processing at all levels of the neuraxis, including peripheral nociceptor termini, dorsal root ganglia, spinal cord, and supraspinal areas. This action of cytokines throughout the neuraxis is believed to play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.


UniProtKB:Q7TUX1


GO:0035106

The study introduces a new method, the operant plantar thermal assay (OPTA), for measuring thermal pain tolerance in mice. The OPTA requires mice to make a decision to obtain a reward under thermally adverse conditions. The study found that female mice showed greater temperature-dependent tolerance than males. The study also found that neuropathic pain, induced by chronic constriction injury (CCI), increased thermal tolerance, while inflammation, induced by complete Freund's adjuvant (CFA), had no effect. The administration of clonidine increased thermal tolerance in both injured and sham animals, while the non-steroidal anti-inflammatory meloxicam reduced thermal pain tolerance.


MESH:D005620


PUBCHEM.COMPOUND:2803


PUBCHEM.COMPOUND:54677470


EFO:0009510

The study found that peripheral nerve injury led to an increase in the expression of long noncoding RNA H19 in the injured dorsal root ganglion (DRG). The use of a specific H19 siRNA was found to alleviate symptoms of mechanical allodynia and thermal hyperalgesia, suggesting that H19 plays a role in the development and maintenance of neuropathic pain. Therefore, H19 could be a potential target for the treatment of neuropathic pain.


NCBIGene:14955


NCBIGene:14955

contributes to development and maintenance of


UniProtKB:A0A5A4LKE5

The paper suggests that GluA1, a protein found in the central amygdala, has a dual role in pain perception and opioid withdrawal. It increases pain but inhibits the aversion typically associated with opioid withdrawal.


PR:000010277

The study found that the DNA methyl-CpG binding protein 2 (MeCP2) plays a crucial role in the transgenerational transmission of chronic pain. In a female mouse model of chronic pain, offspring showed significant pain sensitization, which correlated with increased MeCP2 expression in primary somatosensory cortical (S1) glutamate neurons. Manipulating MeCP2 expression in these neurons in the maternal mice affected the pain sensitization in the offspring. The study also found that MeCP2 regulated the expression of a wide range of genes in these neurons, suggesting its importance in pain transgenerational transmission.


PR:000010277

Primary somatosensory cortical (S1) glutamate neurons


NCIT:C59068

The study found that Toll-like receptor 7 (TLR7) contributes to neuropathic pain. Peripheral nerve injury led to a significant increase in the expression of TLR7 in mouse injured dorsal root ganglion (DRG). Blocking this increase alleviated pain hypersensitivities. Conversely, mimicking this increase led to augmented responses to stimuli and induced spontaneous pain. The increased TLR7 activated the NF-κB signaling pathway, suggesting that TLR7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons.


NCBIGene:51284


UBERON:0000979

The study found that tibia fractures can induce an adaptive autoimmune response, characterized by germinal center formation in popliteal lymph nodes and T follicular helper cell (Tfh) dependent B cell activation, leading to nociceptive sensitization within 3 weeks. This response was found to be dependent on the production of IgM. The study also found that treating fracture mice with the Tfh signaling inhibitor FK506 reduced germinal center reactions, IgM levels, and nociceptive sensitization.


UBERON:0010754


CL:0002038


PUBCHEM.COMPOUND:18401870


MESH:C000708981

The study found that general anesthesia (GA) can suppress pain by activating a specific group of GABAergic neurons in the central amygdala (CeAGA neurons) of mice. These neurons are activated by different GA drugs and have a basal activity that reflects the internal state of the animal. When these neurons were activated, they suppressed pain and abolished neuropathic pain-induced mechanical hypersensitivity. In contrast, inhibiting these neurons exacerbated pain and cancelled the analgesic effect of low-dose ketamine. The researchers suggest that CeAGA neurons could be a potential therapeutic target for chronic pain relief.


NCBIGene:234219


PUBCHEM.COMPOUND:3821

analgesic effect cancelled when GABAergic neurons are inhibited


MONDO:0043797

The study investigates the effect of sex on neurodegeneration, locomotor impairment, and neuropathic pain following a spinal cord injury (SCI) in male and female C57BL/6 mice. The study found that while motor function was largely similar between sexes, all males and only half of the females recovered plantar stepping. The rostral-caudal lesion length was shorter in females than in males. However, there were no significant differences in behavioral signs of neuropathic pain between sexes.


MONDO:0043797


UniProtKB:A0A9L0SH84

The study used next-generation transcriptomics and imaging-based approaches to compare the expression of population markers in mouse and human dorsal root ganglion (DRG). The researchers found a large overlapping CGRP and P2X3R neuronal subpopulation in human lumbar DRG that was not present in mouse. They also found differential expression in a variety of mRNAs for transient receptor potential channels, cholinergic receptors, potassium channels, sodium channels, and other markers/targets. These findings suggest that sensory system organizational principles are likely different between both species.


UniProtKB:A0A8C2QET8


UniProtKB:A0A922ISJ9


UniProtKB:A0A3V0YXY6


UBERON:0011926

The study found that a localized sympathectomy, which involves cutting the gray rami containing sympathetic postganglionic axons, reduced mechanical hypersensitivity in two different rat neuropathic pain models. This procedure also reduced functional and anatomical measures of regeneration, as well as the expression of growth-associated protein 43 (GAP43), a protein related to regeneration. In addition, the sympathectomy reduced the formation of neuromas and the density of macrophages in the sensory ganglia and peripheral nerve. These findings suggest that sympathetic nerves may locally affect immune function and that managing pain in neuropathic conditions without inhibiting peripheral nerve regeneration is a challenge.


UBERON:0011926


UniProtKB:A0A6J8BCL2

The study investigates the role of cyclin-dependent kinase 5 (Cdk5) in neuropathic pain. Cdk5 and its activators p35 and p39, which are expressed in spinal nerves, dorsal root ganglia, and the dorsal horn of the spinal cord, are found to have increased expression/activity in neuropathic pain conditions. Cdk5 is regulated through its own phosphorylation, through increasing p35's interaction with Cdk5, and through cleavage of p35 into p25. Cdk5 affects various proteins involved in pain signaling, including channels (eg, transient receptor potential cation channel and voltage-gated calcium channel), proteins involved in neurotransmitter release (eg, synaptophysin and collapsin response mediator protein 2), and receptors (eg, glutamate, purinergic, and opioid). Therefore, Cdk5 could be a potential target for treating neuropathic pain conditions.


PR:000050089


UniProtKB:A0A377SVP8


UniProtKB:A0A6J8BCL2

Transient receptor potential cation channel


UniProtKB:A0A6J8BCL2


UniProtKB:Q9PS46

The study provides insights into the role of spinal neuropeptide Y (NPY) in inhibiting chronic pain and itch. The research focuses on the Gi-coupled neuropeptide Y1 receptor (Y1), which is found in primary afferent neurons and a subpopulation of small, excitatory, glutamatergic/somatostatinergic interneurons (Y1-INs) in the dorsal horn. The selective removal of spinal Y1-INs with an NPY-conjugated saporin neurotoxin reduces peripheral nerve injury-induced hypersensitivity. On the other hand, reducing NPY expression or administering Y1 antagonists reinstates hypersensitivity in models of chronic latent pain sensitization. The study suggests that spinal NPY release and the subsequent inhibition of pain facilitatory Y1-INs is a significant mechanism of endogenous analgesia. This mechanism can be replicated with pharmacological approaches, such as the administration of Y1 agonists, to inhibit hypersensitivity and spinal neuron activity in rodent models of neuropathic, inflammatory, and postoperative pain. Activation of Y1 also inhibits mechanical- and histamine-induced itch. The findings suggest that Y1-INs could be a potential therapeutic target for the development of NPY-Y1 agonists to treat chronic pain and itch.


UniProtKB:Q5FVH5


MESH:C085696


MESH:D008822

The study investigates the neuropathic phenotype of the K/BxN transgenic mouse, which develops spontaneous autoimmune arthritis. Both male and female mice display severe tactile allodynia, which is reduced by gabapentin but not by ketorolac. In the dorsal horn, both genders show increased GFAP+ astrocytic cells, but only males show an increase in Iba1+ microglia. In the dorsal root ganglia (DRG), there is an increase in CGRP+, TH+, and Iba1+ (macrophage) labeling, but no increase in ATF3+ cells. At the ankle, there is increased CGRP+, TH+, and GAP-43+ fiber synovial innervation. These findings suggest that the adult K/BxN transgenic arthritic mice display a neuropathic phenotype, which is consistent with the analgesic pharmacology seen in this animal model.


HP:0012533


NCIT:C41841


CL:0002628


UniProtKB:A0A9L0SH84


UniProtKB:A0A7R8D2W3


NCBITaxon:336296


GO:1990622


GO:0060384


UniProtKB:I7GDE3

The study found that legumain (Lgmn), a cysteine protease, cleaves protease-activated receptor-2 (PAR2) in the acidic microenvironment of oral squamous cell carcinoma (OSCC), causing pain. Lgmn was found to be activated in OSCC patient tumors compared to normal oral tissue. Lgmn evoked pain in wild-type female mice but not in mice lacking PAR2 in NaV1.8-positive neurons or in mice treated with a Lgmn inhibitor, LI-1. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons and activated PAR2 by biased mechanisms to induce calcium mobilization, cAMP formation, and activation of protein kinase A (PKA) and protein kinase D (PKD), but not β-arrestin recruitment or PAR2 endocytosis.


UniProtKB:I7GDE3


UniProtKB:I7GDE3

does not recruit or induce endocytosis of


NCBIGene:12772

The study investigates the role of CCR2-expressing macrophages in a mouse model of low back pain and radiculopathy. The researchers found that local inflammation of the dorsal root ganglia (DRG) induced pain behaviors in mice, which were dominated by increases in CCR2+ macrophages. The primary endogenous ligand for CCR2, CCL2, was upregulated in inflamed DRG. Experimental manipulations that reduced the CCR2+ macrophage influx also reduced pain behaviors. These included global CCR2 knockout, systemic injection of INCB3344 (a specific CCR2 blocker), and intravenous injection of liposomal clodronate. The study suggests a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy.


NCBIGene:6347


CHEMBL.COMPOUND:CHEMBL1289316


MESH:C559761


MONDO:0024317

The paper discusses the role of neuroimmune signaling in chronic pain conditions such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders. It emphasizes that the interaction between immune cells, glia, and neurons is crucial for the onset and persistence of chronic pain. The paper also discusses recent advancements in understanding these neuroimmune signaling mechanisms and potential therapeutic targets in rodent models of chronic pain. Additionally, it mentions new technologies to study, diagnose, and quantify the neuroimmune contributions to chronic pain in patients.


UniProtKB:Q1A7A4

The study suggests that complex regional pain syndrome (CRPS) may be a posttraumatic autoimmune disease. The research found that early CRPS patient IgM antibodies have pronociceptive effects in the skin and spinal cord of muMT fracture mice lacking B cells. The study also found that complement component C5a and its receptor expression increased in skin and spinal cord after fracture, predominantly on dermal macrophages and spinal microglia. The pronociceptive effects of IgM were blocked by a C5a receptor antagonist (PMX53) or a global cytokine inhibitor (pentoxifylline). Chronic CRPS patient IgM (but not IgG) caused nociceptive sensitization in muMT fracture mice. The researchers suggest that CRPS IgM antibodies bind to neoantigens in the fracture limb skin and corresponding spinal cord to activate C5a complement signaling in macrophages and microglia, leading to proinflammatory cytokine expression contributing to nociceptive sensitization in the injured limb.


UniProtKB:A0A1T3C6T0

The paper discusses the role of G protein-coupled receptors (GPCRs) in chronic pain associated with digestive system disorders, inflammation, and cancer. The study suggests that GPCRs, when activated by mediators from injured tissues, can lead to sensitization of ion channels and acute hyperexcitability and nociception. Sustained agonist release can cause GPCR redistribution to endosomes, where persistent signaling regulates activity of channels and genes that control chronic hyperexcitability and nociception. The paper also discusses the potential of endosomally targeted GPCR antagonists, biased agonists of µ-opioid receptors (MOPrs), and allosteric modulators of GPCRs in providing superior pain relief. The study also highlights the potential of GPCR dimers as distinct therapeutic targets for nociception.


UniProtKB:A0A8T2DCI9


MESH:D011992

site of GPCR redistribution in chronic pain


UniProtKB:A0A3G2QWQ4

potential distinct therapeutic targets for


CL:0000134

Chemotherapy-induced peripheral neuropathy (CIPN)

The study demonstrates that nasal administration of mesenchymal stem cells (MSC) can completely reverse the signs of chemotherapy-induced peripheral neuropathy (CIPN), a common adverse effect of cancer treatment, in mice. This reversal includes mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with the normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. The MSC enter the meninges of the brain, spinal cord, and peripheral lymph nodes to promote IL-10 production by macrophages. The reversal of CIPN symptoms critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, wild type MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons.


CL:0000134


UniProtKB:A0A0B5H157


HGNC.FAMILY:245

The paper discusses neuropathic pain, a common clinical disorder that significantly impacts the quality of life of patients. The study focuses on the downregulation of opioid receptors in primary afferent neurons following peripheral nerve trauma, which limits the effectiveness of opioids in treating this disorder. The paper explores the molecular mechanisms behind this downregulation, including alterations in epigenetic modifications (DNA methylation, histone methylation, and microRNAs), expression of transcription factors, post-transcriptional modifications (RNA methylation), and protein translation initiation in the neurons of the dorsal root ganglion (DRG). The study suggests that understanding these mechanisms could provide new avenues for the prevention and treatment of neuropathic pain.


MONDO:0004820


UniProtKB:A0A1R4ABV0

The study investigates the role of non-SUMOylated collapsin response mediator protein 2 (CRMP2) in the functional expression of the voltage-gated sodium channel NaV1.7, which is crucial in neuronal excitability and pain signaling. The research found that non-SUMOylated CRMP2 forms a complex with endocytic proteins Numb, Eps15, and Nedd4-2 to promote the endocytosis of NaV1.7. Inhibiting clathrin assembly in nerve-injured mice precipitated mechanical allodynia, a type of neuropathic pain. The expression of Numb, Nedd4-2, and Eps15 was not modified in the dorsal root ganglia (DRG) of the mice. Silencing these proteins in DRG neurons restored the loss of sodium currents.


UniProtKB:A0A1R4ABV0


PR:000005580


UniProtKB:A0A0S7GWW1


NCBIGene:80036

The study investigates the role of Transient receptor potential melastatin 3 (TRPM3), a heat-activated ion channel in primary sensory neurons, in various pain modalities. The research used two inhibitors of TRPM3, isosakuranetin and primidone, in mice with nerve injury-induced neuropathic pain. The results showed that these inhibitors reduced heat hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve in wild-type mice, but not in TRPM3-/- mice. The study also found that genetic deletion or inhibitors of TRPM3 reduced the increase in the levels of the early genes c-Fos and pERK in the spinal cord and dorsal root ganglia (DRGs) in CCI mice, suggesting spontaneous activity of the channel. The findings indicate a role for TRPM3 in heat hypersensitivity and spontaneous pain after nerve injury.


NCBIGene:80036


PUBCHEM.COMPOUND:160481


PUBCHEM.COMPOUND:4909


NCBIGene:106571028


UniProtKB:B5U818


MESH:C038777

The study investigates the effects of a neurokinin 1 receptor (NK1R) antagonist, Spantide I (Span), conjugated to cholestanol (Span-Chol), on pain relief. The research found that Span-Chol accumulates in endosomes, inhibits endosomal NK1R signaling, and causes prolonged antinociception. Over time, Span-Chol increased local concentration at the plasma membrane, showed an increase in NK1R-binding affinity, and more potent inhibition of NK1R-mediated calcium signaling. Span-Chol also caused a persistent decrease in NK1R recruitment of β-arrestin and receptor internalization to early endosomes. In a preclinical model of pain, Span-Chol caused prolonged antinociception, which is attributable to a three-pronged mechanism of action: increased local concentration at membranes, a prolonged decrease in NK1R endocytosis, and persistent inhibition of signaling from endosomes.


MESH:C038777


NCBIGene:24498

The study investigates the role of interleukin 6 (IL-6) signaling in the development of adaptive immune responses and nociceptive sensitization in a murine tibia fracture model of complex regional pain syndrome (CRPS). The findings suggest that IL-6 signaling is necessary for the development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. The study also found that the administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after fracture and inhibited lymphadenopathy.


NCBIGene:24498


MESH:D000888


GO:0010161

The study reviews the mechanisms and pathways of pain modulation by light exposure, known as photobiomodulation. It was found that cutaneous application of red light (660 nm) can reduce pain in neuropathies and complex regional pain syndrome-I, but visual application of the same wavelength can exacerbate migraine headaches and cause functional pain in animal models. Conversely, visual exposure to green light can reduce pain in conditions like migraines and fibromyalgia. Both routes of exposure cause changes in the brainstem, spinal cord, dorsal root ganglia, and nociceptors.


PUBCHEM.COMPOUND:139033511


PR:000013430

The study found that intermittent parathyroid hormone (iPTH) can reduce osteoarthritis pain by inhibiting sensory innervation, deterioration of subchondral bone, and degeneration of articular cartilage in a mouse model. The iPTH treatment also reduced the level of prostaglandin E2 in the subchondral bone of the mice and regulated uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling. The effects of iPTH were found to be specifically through the PTH type 1 receptor in Nestin+ mesenchymal stromal cells.


PR:000013430


UniProtKB:A0A7J5YVG1


PUBCHEM.COMPOUND:168347353

The study investigates the effects of Dimethyl fumarate (DMF) on Complex regional pain syndrome (CRPS) in a murine model. CRPS is a painful condition often caused by surgery or trauma to a limb, and is associated with both innate and adaptive immunological changes. DMF, which activates antioxidant systems and suppresses immune system activation, was hypothesized to reduce nociceptive, functional, and immunological changes in a model of CRPS. The study found that DMF administration prevented nociceptive sensitization, reduced uneven hindlimb weight bearing, and reduced the accumulation of markers of oxidative stress, activation of innate immune mediator production, lymph node hypertrophy, and the accumulation of IgM in fractured limbs. Interestingly, the effects of DMF were largely unchanged in Nrf2 null mutant mice, suggesting that the Nrf2 transcription factor is not required for DMF's effects.


PUBCHEM.COMPOUND:168347353


UniProtKB:A9JQD6

The study investigates the use of targeted epigenetic repression of NaV1.7, a sodium channel protein associated with pain signaling, as a potential treatment for chronic pain. The researchers used epigenome engineering approaches based on CRISPR-dCas9 and zinc finger proteins to repress NaV1.7 in primary afferents at the spinal level. The efficiency of NaV1.7 repression was first optimized in vitro in Neuro2A cells. The epigenome engineering platforms were then delivered via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain. The results showed effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice.


NCBITaxon:1520554


NCBIGene:859120


NCBITaxon:82300


UniProtKB:A9JQD6


NCBIGene:741390

Cocaine- and amphetamine-regulated transcript (Cartpt)

The peptide encoded by the cocaine- and amphetamine-regulated transcript (Cartpt) gene, known as CART peptide (CART), has been recognized since 1981. The gene encoding CART was identified in 1995. The CART peptide has been linked to ingestive behaviors, reward behaviors, and pain sensation. Despite the significance of CART, the full potential for this peptide or its analogs to be developed into therapeutic agents remained unrealized due to the absence of an identified receptor. Recently, the G protein-coupled receptor (GPCR), GPR160, has been identified as a receptor for CART, opening up potential for the development of pharmcotherapies targeting GPR160.


UniProtKB:A0A7L8Y656


NCIT:C158332

The study found that macrophages (MΦ) residing in the sciatic nerve play a significant role in cancer-induced pain. Depletion of these resident macrophages (rMΦ) in mice reduced pain sensitivity caused by the injection of melanoma or lung carcinoma cells. The study also found that MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and contributed to cancer-induced pain through rMΦ expansion, activation of transient receptor potential ankyrin 1 (TRPA1), and oxidative stress. The deletion of Trpa1 revealed that Schwann cell TRPA1 is crucial for sciatic nerve rMΦ expansion and pain-like behaviors. The study concluded that a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 signals cancer-induced pain.


NCBIGene:1435


NCBIGene:1435

Transient receptor potential ankyrin 1 (TRPA1)


CL:0000692


PUBCHEM.COMPOUND:71605072

The study investigates the effectiveness of a fentanyl analogue, NFEPP, which preferentially activates the µ-opioid receptor (MOPr) in acidified diseased tissues, in treating pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues. The results show that NFEPP inhibited pain responses in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Unlike fentanyl, NFEPP did not decrease defecation, cause respiratory depression, or induce hyperactivity in mice with colitis. The study concludes that NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce pain relief without causing respiratory depression, constipation, and hyperactivity.


PUBCHEM.COMPOUND:71605072


PUBCHEM.COMPOUND:3345


PR:000001379

The study investigates the effect of low-dose interleukin-2 (ld-IL2) and regulatory T (Treg) cells on mechanical allodynia, a condition of heightened sensitivity to pain, in a mouse model of sciatic nerve injury. The results show that treatment with ld-IL2 or adoptive transfer of Treg cells can significantly reduce the severity of allodynia. The study also found that ld-IL2 increased the frequency of Treg cells in the injured sciatic nerves, suggesting that the injured nerve is the site of action for ld-IL2.


HP:0020112


PR:000001379

increases frequency in injured sciatic nerves


UniProtKB:A0A0S7ERQ8

The study investigates the effect of a localized "microsympathectomy" and the manipulation of CCL2 (monocyte chemoattractant protein 1) in a rat tibial nerve crush model of neuropathic pain. The results show that microsympathectomy and localized siRNA-mediated knockdown of CCL2 in the lumbar dorsal root ganglion led to partial improvement of mechanical hypersensitivity and guarding behavior, reduction of regeneration markers growth-associated protein 43 and activating transcription factor 3, and reduction of macrophage density in the sensory ganglia and regenerating nerve. The study suggests that local sympathetic effects on neuropathic pain may be mediated largely by the effects on expression of CCL2, which in turn regulates the regeneration process.


UniProtKB:A0A0S7ERQ8


MONDO:0024317

The paper discusses the challenge of chronic pain, a disabling disease with limited treatment options. The authors propose a multi-institutional collaboration to better understand the cells and networks of pain in humans, which could potentially lead to improved therapeutic development.


UniProtKB:A0A8S3UZF1

The study found that neuroinflammation, a major component in the transition to and perpetuation of neuropathic pain states, involves the activation of TLR4 in cholesterol-enriched lipid rafts, termed as inflammarafts. The deletion of cholesterol transporters ABCA1 and ABCG1 in microglia led to the formation of inflammarafts and induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice. However, AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia.


NCBIGene:9619


UniProtKB:U5KLT9

facilitates depletion from inflammarafts


UniProtKB:U5KLT9


PR:000005046

The paper discusses the diverse pharmacological actions of the Cocaine- and amphetamine-regulated transcript peptide (CARTp) in the central and peripheral nervous systems and several endocrine organs, including the pancreas. The identification of a CARTp receptor, GPR160, has revealed the physiological importance and therapeutic potential of CARTp or its analogs. The CARTp-GPR160 interaction is essential for the circadian regulation of appetite and thirst and for the transmission of nerve injury-induced pain. Further molecular approaches are being used to uncover additional physiologically relevant actions of this ligand/receptor pair.


PR:000005046


NCIT:C26791

The study investigates the role of FTO (fat-mass and obesity-associated protein), an N6-methyladenosine demethylase, in hemorrhage-induced thalamic pain. The research found that FTO expression was increased in the thalamus after hemorrhage caused by microinjection of Coll IV (type IV collagenase). The administration of meclofenamic acid (an FTO inhibitor) or microinjection of adeno-associated virus 5 (AAV5) expressing Cre into the thalamus of Ftofl/fl mice reduced TLR4 (Toll-like receptor 4) upregulation and nociceptive hypersensitivity. Conversely, thalamic microinjection of AAV5 expressing FTO increased TLR4 expression and elicited hypersensitivities to various stimuli. The findings suggest that FTO stabilizes TLR4 upregulation in thalamic neurons, contributing to hemorrhage-induced thalamic pain.


UniProtKB:A0A8C9HE10


PUBCHEM.COMPOUND:4037


UniProtKB:A0A7J7JTT2


GTOPDB:681

The CGRP system, part of the calcitonin family of peptides, is a significant target for migraine treatment. However, not all migraine sufferers respond to anti-CGRP treatments, indicating the need for additional targets. Other peptides in the calcitonin family, including calcitonin, amylin, adrenomedullin, and adrenomedullin 2, show pro-nociceptive and anti-nociceptive actions in primary headache conditions like migraine. These peptides and their receptors may be useful in treating migraine and other pain disorders.


UniProtKB:B2D2C1


UniProtKB:B8PQ42


PR:000003781


NCBIGene:445917


UniProtKB:S4R319

The study investigates the role of mitochondrial calcium uniporter in painful diabetic neuropathy (PDN), a complication affecting 25% of diabetic patients. The researchers found that mitochondrial fission proteins were elevated in dorsal root ganglion (DRG) neurons in mice with PDN. They also observed increased calcium signaling in DRG nociceptors and fragmented mitochondrial morphology. By selectively deleting the mitochondrial calcium uniporter, they were able to restore normal mitochondrial morphology, prevent axonal degeneration, and reverse mechanical allodynia in the mouse model. The study suggests that targeting calcium entry into nociceptor mitochondria could be a potential therapeutic approach for PDN.


PR:000010366


PUBCHEM.COMPOUND:5460341


MESH:D008928


UniProtKB:S4R319


NCBIGene:11535

The study investigates the pharmacology of the calcitonin (CT) receptor family in mice, which includes two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs), and multiple endogenous peptides. The researchers synthesized and characterized mouse adrenomedullin, adrenomedullin 2, and βCGRP, and mouse CTR with or without mouse RAMPs. They found that the pharmacology of these receptors in mice is subtly different from that in humans, with mouse receptors showing less discrimination between ligands. This finding poses challenges for translating findings from mice to humans and underscores the need for new ligands to differentiate between these complexes.


UniProtKB:A0A199V1M4


UniProtKB:A0A0D3MTH6

The study focuses on the role of the Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel in acute and chronic itch. TRPV4, which is expressed in ganglion sensory neurons and various skin cells, has been relatively understudied in the context of itch modulation. However, recent evidence suggests that TRPV4 contributes to acute and chronic disease-associated itch. The exact cellular and molecular mechanisms of TRPV4's involvement in itch are still not fully understood.


UniProtKB:A0A0D3MTH6


PUBCHEM.COMPOUND:6443995

The study found that the concentration of prostaglandin E2 (PGE2) was elevated in porous endplates, leading to spinal pain. High-dose treatment with the cyclooxygenase 2 inhibitor, celecoxib, decreased the PGE2 concentration and reduced spinal pain in mice with lumbar spine instability. However, this treatment also impaired bone formation in porous endplates, and spinal pain returned after discontinuing the treatment. Low-dose celecoxib treatment, on the other hand, led to a long-lasting reduction in spinal pain and significantly reduced endplate porosity, which was associated with decreased sensory nerve innervation and spinal pain.


PUBCHEM.COMPOUND:6443995


PUBCHEM.COMPOUND:2662


UniProtKB:Q9PSQ0

The study identified genes that are exclusively expressed in different types of mouse ganglion neurons. The pituitary hormone genes prolactin (Prl), growth hormone (Gh), and proopiomelanocortin (Pomc) were found to be almost exclusively in trigeminal ganglion (TG) neurons. The study also found that growth hormone (GH) plays a significant role in pain responses in the trigeminal system, as it produced mechanical hypersensitivity when injected intrathecally and generated orofacial and headache-like periorbital mechanical hypersensitivity. This hypersensitivity was reversed by a GH receptor antagonist, pegvisomant.


PR:000007968


UniProtKB:Q9PWN1


PR:000007968

Orofacial and headache-like periorbital mechanical hypersensitivity


UNII:N824AOU5XV


PR:000008250

The study investigates the sex differences in protein kinase A (PKA) signaling of latent postoperative pain sensitization, which is controlled by kappa opioid receptors (KOR) in the spinal cord. The research found that both males and females have NMDA receptor (NMDAR)→adenylyl cyclase-1 (AC1)→PKA and Epac signaling pathways in the dorsal horn of the spinal cord that maintain latent sensitization. However, only males recruit a PKA-dependent mechanism. The study suggests that AC1, PKA, and Epac inhibitors could be developed into a new pharmacotherapy for chronic postoperative pain.


NCBIGene:281601


PR:000006033

The study found that the protease Cathepsin S, which is more active in oral squamous cell carcinoma (SCC) than in normal tissue, contributes to cancer pain through the activation of protease-activated receptor-2 (PAR2). This was demonstrated in both human oral SCC patients and preclinical mouse models. The study also found that the human oral SCC cell line (HSC-3) with a homozygous deletion of the gene for Cathepsin S (CTSS) provoked significantly less pain, indicating that Cathepsin S plays a significant role in cancer pain.


PR:000006033


MONDO:0004958


UBERON:0004132

The study identified nine distinct subtypes of trigeminal (TG) sensory neurons that innervate the masseter muscle (MM) fibers, fascia, tendons, and adjusted tissues. These neurons were identified using patch clamp electrophysiology and immunohistochemistry on TG neurons back-traced from a reporter mouse MM. The study found that 24% of these neurons belonged to non-peptidergic IB-4+/TRPA1- or IB-4+/TRPA1+ groups, while two TRPV1+ small-sized neuronal groups were classified as peptidergic/CGRP+. The study also found that masseteric muscle fibers, tendons and masseteric fascia in mice and the common marmoset were exclusively innervated by either CGRP+/NFH+ or CGRP-/NFH+ medium-to-large neurons.


UniProtKB:A0A6J8ELD2


NCBIGene:101720480


UniProtKB:A0A9L0SH84


UniProtKB:A0A0S7J0C3


PUBCHEM.COMPOUND:44584947

The study identifies nociceptor endocytosis as a potential target for local, specific, and long-lasting treatment of inflammatory pain. The researchers found that AP2α2, an α-subunit isoform of the AP2 complex, is preferentially expressed within CGRP+/IB4- nociceptors in rodents and in CGRP+ dorsal root ganglion neurons from a human donor. By using genetic and pharmacological approaches to inhibit nociceptor endocytosis, they demonstrated its role in the development and maintenance of acute and chronic inflammatory pain. A one-time injection of an AP2 inhibitor peptide significantly reduced acute and chronic pain-like behaviors and provided prolonged analgesia. The study also found sexually dimorphic recovery responses to this pharmacological approach, emphasizing the importance of sex differences in pain development and response to analgesics.


PUBCHEM.COMPOUND:44584947


PUBCHEM.COMPOUND:4624

The study investigates the role of the autonomic nervous system in regulating the adaptive immune system activation and nociceptive sensitization in a mouse model of chronic post-traumatic pain with features of complex regional pain syndrome (CRPS). The researchers used 6-hydroxydopamine (6-OHDA) or lofexidine to reduce sympathetic signaling and nicotine to augment parasympathetic signaling. The results showed that these treatments reduced fracture-induced hindpaw nociceptive sensitization and unweighting, prevented IgM deposition, hypertrophy of popliteal lymph nodes, and the development of pronociceptive serum transfer effects. This suggests that inhibiting sympathetic or augmenting parasympathetic signaling inhibits pro-nociceptive immunological changes accompanying limb fracture.


PUBCHEM.COMPOUND:30668


PUBCHEM.COMPOUND:89594


PUBCHEM.COMPOUND:4624


REACT:R-SSC-210439

Neurokinin 1 receptor–positive (NK1R+) neurons

The study found that astrocytes, a type of cell in the spinal cord, play a significant role in pain gating, a process that reduces the transmission of pain signals to the brain. The researchers discovered that electrical stimulation of large-diameter afferent fibers (Aβ-fibers) in mice activated astrocytes, which then induced long-term depression (LTD) in neurokinin 1 receptor–positive (NK1R+) neurons and reduced pain through the activation of endogenous adenosinergic mechanisms. When astrocyte activation was suppressed, the induction of LTD in NK1R+ neurons and pain inhibition by Aβ-fiber stimulation was blocked.


REACT:R-SSC-210439

reduces through activation of endogenous adenosinergic mechanisms


EFO:0009510

causes abnormal spontaneous activity (cluster firing)

The study discovered a unique form of abnormal spontaneous activity in dorsal root ganglion (DRG) neurons following peripheral nerve injury, termed as "cluster firing". This cluster firing was found to be directly correlated with nerve injury-induced spontaneous pain behaviors. The study also found that this cluster firing is triggered by the activity of sympathetic nerves, which sprout into DRGs after injury, and identified norepinephrine as a key neurotransmitter mediating this unique firing. The study suggests that blocking sympathetically mediated cluster firing could be a new approach for treating spontaneous pain.


UniProtKB:A0A077Z2Z7

The study investigates a new approach to pain management by indirectly regulating the NaV1.7 channel, which is crucial for pain sensation. The researchers found that blocking the addition of small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting protein, CRMP2, inhibited NaV1.7 functions and reduced pain in rodents. A compound, 194, was identified that selectively engaged NaV1.7 in vitro and ex vivo. When orally administered, compound 194 demonstrated antinociceptive effects in models of acute and chronic pain, and showed synergy with other analgesics without causing addiction, rewarding properties, or neurotoxicity. The analgesic effect of 194 was found to be opioid receptor dependent.


UniProtKB:A0A1R4ABV0


PUBCHEM.COMPOUND:24755517


UBERON:0002405

The study investigates the role of the immune system in pain regulation, focusing on the interaction between the immune system and the peripheral sensory nervous system. The research, conducted on rodents, reveals that T cells and macrophages can both enhance pain through proinflammatory mediators and promote pain resolution through anti-inflammatory mediators and endogenous opioids.


NCIT:C158332


UniProtKB:A0A8H7HU83

Transient receptor potential (TRP) ion channels

involved in generation and progression of

The study discusses the role of transient receptor potential (TRP) ion channels in the generation and progression of chronic pain. Despite being targeted by pharmaceutical companies for therapeutic purposes, TRP channel inhibitors have failed in clinical trials due to their thermoregulatory function. The study also highlights the emergence of Botulinum neurotoxins (BoNTs) as potential pain therapeutics due to their regulation of exocytosis and pro-nociceptive neurotransmitters. It is suggested that BoNTs may also regulate the expression and function of TRP channels, which could explain their analgesic effects.


UniProtKB:A0A7R8H6H2

The study investigates the role of transient receptor potential cation channel subfamily C member 4 (TRPC4) in pain and its potential as a target for migraine treatment. The researchers found that TRPC4 is highly expressed in trigeminal ganglia and its activation mediates not only itch but also pain. The small-molecule inhibitor ML204, a specific TRPC4 antagonist, significantly reduced migraine-like behaviors in mice after injection of nitroglycerin (NTG), a migraine inducer. Additionally, ML-204 treatment resulted in a significant decrease in calcitonin gene-related peptide (CGRP) protein levels in the plasma, which largely prevented the development of chronic migraine-like behavior.


UniProtKB:A0A7R8H6H2


PUBCHEM.COMPOUND:49786978


RXCUI:1114466


CHEBI:35482

The paper discusses the potential of nanotechnology in pain management. Current pain treatments, which primarily rely on opioid analgesics, are unsatisfactory due to their life-threatening side effects and addictive properties. Nanomedicine could provide targeted treatments without these burdens. The paper highlights advances in nanoparticle-based drug delivery to reduce side effects, gene therapy to address the source of pain, and nanomaterials-based scavenging to mediate pain signaling.


MONDO:0006862


PUBCHEM.COMPOUND:134817171

The study investigates the role of Histone deacetylase 6 (HDAC6) inhibitors in reversing chemotherapy-induced peripheral neuropathy (CIPN). The researchers found that HDAC6 inhibitors can reverse CIPN by increasing macrophage-derived IL-10 signaling to IL-10 receptors on Advillin+ sensory neurons. This process helps to resolve mechanical hypersensitivity. Additionally, HDAC6 inhibitors can restore axonal mitochondrial health, which is independent of macrophages and IL-10 signaling.


UniProtKB:A0A0B5H157


PUBCHEM.COMPOUND:134817171


PUBCHEM.COMPOUND:5460033


UniProtKB:A9JQD6

The study investigates the role of the voltage-gated sodium channel isoform NaV1.7 in transmitting pain signals. The researchers found that a small molecule inhibitor of CRMP2 SUMOylation, compound 194, selectively reduces NaV1.7 currents in DRG neurons across different species. This compound also reversed mechanical allodynia in a spared nerve injury and chemotherapy-induced model of neuropathic pain. The study further shows that oral administration of 194 reverses mechanical allodynia in a chronic constriction injury (CCI) model of neuropathic pain. The results suggest that 194 is a robust inhibitor of NaV1.7 function, effectively reducing pain associated with nerve injury.


PUBCHEM.COMPOUND:24755517

Chemotherapy-induced model of neuropathic pain


UniProtKB:A0A1R4ABV0

Spontaneous excitatory postsynaptic currents

reduces frequency and amplitude when knocked down

The study investigates the role of collapsin response mediator protein 2 (CRMP2) in neuropathic pain. The researchers found that knocking down CRMP2 in the spinal cord of rats reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents, but not spontaneous inhibitory postsynaptic currents. A similar effect was observed when CRMP2 was conditionally knocked out from mouse neurons. However, knocking out CRMP2 from mouse astrocytes had no effect on synaptic transmission. The study concludes that CRMP2 is a key regulator of glutamatergic neurotransmission driving pain signaling and contributes to the transition of physiological pain into pathological pain.


UniProtKB:A0A1R4ABV0

contributes to the transition of physiological pain into pathological pain


UniProtKB:A0A1R4ABV0

knockout has no effect on synaptic transmission


GTOPDB:1575

The study investigates the analgesic mechanism of contulakin-G (CGX), a conotoxin peptide and neurotensin analogue. The researchers hypothesized that CGX produces antinociception through the activation of the presynaptic neurotensin receptor (NTSR)2. The study found that intrathecal administration of CGX inhibited thermal and mechanical hypersensitivities in rodents. The inhibition of CGX was found to be dependent on the R-type voltage-gated calcium channel (Cav2.3) in sensory neurons. The study also found coexpression of NTSR2 and Cav2.3 in dorsal root ganglion neurons.


GTOPDB:1575

R-type voltage-gated calcium channel (Cav2.3)


PR:000001627


NCBIGene:777

R-type voltage-gated calcium channel (Cav2.3)


UniProtKB:Q5U791

The study investigates the trafficking and signaling of protease-activated receptor 2 (PAR2) in colitis. Researchers generated knockin mice expressing PAR2 fused to monomeric ultrastable green fluorescent protein (muGFP). The PAR2-muGFP was found to be expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR2-muGFP was prominently localized to the basolateral membrane of colonocytes. However, in mice with colitis, PAR2-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes. PAR2 agonists stimulated endocytosis of PAR2 and recruitment of Gαq, Gαi, and β-arrestin to early endosomes of T84 colon carcinoma cells. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR2 endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia.


UniProtKB:Q5U791


PR:000006603


UniProtKB:A0A9L0SH84

The study reveals that the calcitonin gene-related peptide (CGRP) released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. The activation of CLR/RAMP1 in human and mouse Schwann cells generates signals from endosomes that evoke cAMP-dependent formation of nitric oxide (NO). NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases reactive oxygen species (ROS), which sustain allodynia via nociceptor TRPA1. A CLR/RAMP1 antagonist encapsulated into nanoparticles provides superior inhibition of CGRP signaling and allodynia in mice.


NCBIGene:25315703


PUBCHEM.COMPOUND:6610315


PUBCHEM.COMPOUND:145068


UniProtKB:A0A6J8ELD2


CHEBI:26523


NCBIGene:18479463


PUBCHEM.COMPOUND:5288826

The study investigates the mechanisms underlying opioid tolerance (OT) and opioid-induced hyperalgesia (OIH) in the gastrointestinal tract. Chronic administration of morphine in mice led to tolerance and evidence of OIH, which was inhibited by the δ-opioid receptor (DOPr) antagonist naltrindole. The pronociceptive actions of opioids were blocked by the DOPr antagonist SDM25N but not the MOPr antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2. The hyperexcitability induced by DAMGO was reversed after a 1 h washout, but reapplication of low concentrations of DAMGO or [D-Ala2, D-Leu5]-Enkephalin restored the hyperexcitability, an effect mediated by protein kinase C. DOPr-dependent DRG neuron hyperexcitability was blocked by the endocytosis inhibitor Pitstop 2, and the weakly internalizing DOPr agonist ARM390 did not cause hyperexcitability. The study concludes that chronic high-dose opioid exposure leads to opioid tolerance and features of OIH in the colon, mediated by DOPr signaling and dependent on receptor endocytosis and downstream protein kinase C signaling.


PUBCHEM.COMPOUND:5288826


GTOPDB:1641


PUBCHEM.COMPOUND:16741282


PUBCHEM.COMPOUND:5462471


PUBCHEM.COMPOUND:71312121


PUBCHEM.COMPOUND:136227331


UniProtKB:Q8VHC2

The study found that the resolution of chemotherapy-induced peripheral neuropathy (CIPN), a type of chronic pain, depends on CD8+ T cells and IL-10 produced by other cells. Specifically, CD8+ T cells producing IL-13 were required for resolution of CIPN. The study also found that cell damage induced by cisplatin activated TIM3 on CD8+ T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN.


PUBCHEM.COMPOUND:5460033


UniProtKB:Q8VHC2


PUBCHEM.COMPOUND:154731588

The study investigates the role of Oxytocin (OT) in pain-related disorders, specifically in the comorbidity of temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS). The research used a rat model with masseter muscle inflammation and forced swim stress to mimic the comorbidity of TMD and FMS. The study found that spinal administration of OT reduced mechanical allodynia and thermal hyperalgesia in the rats' hindpaws. The protein levels of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn increased after OT injection. The analgesic effect of OT was blocked by the OT receptor antagonist atosiban or the 5-HT2A receptor antagonist ritanserin, suggesting that OT may inhibit pain through OT receptors and/or 5-HT2A receptors.


PUBCHEM.COMPOUND:154731588


PUBCHEM.COMPOUND:5311010


PUBCHEM.COMPOUND:5074


PUBCHEM.COMPOUND:86277887

The study investigates the role of FK506-binding protein 51 (FKBP51) in enduring stress-induced hyperalgesia (ESIH), a condition often leading to chronic pain after severe stress exposure. The research used an animal model of traumatic stress exposure and administered SAFit2, a specific inhibitor of FKBP51, at different times relative to stress exposure. The results showed that immediate administration of SAFit2 after stress exposure completely reversed ESIH for more than seven days. However, delayed administration had less effect, and administration 120 hours after stress exposure had no effect. The study suggests that FKBP51 plays a time-dependent role in ESIH pathogenesis and that early inhibition of FKBP51 after traumatic stress could prevent ESIH.


NCBIGene:2289

Chronic multisite musculoskeletal pain (CMP)

The study investigates the vulnerability factors for chronic multisite musculoskeletal pain (CMP). It was found that the interaction between FKBP5 genetic risk and right hippocampal volume was associated with CMP severity. Furthermore, the severity of childhood trauma was found to moderate the relationship between FKBP5 genetic risk, right hippocampal brain volume, and CMP.


EFO:0005035


EFO:0007979

moderates the relationship with FKBP5 genetic risk and Hippocampal volume


OMIM:164170

The study found that voluntary wheel running before nerve injury can prevent chronic pain in both male and female rats. This is achieved by maintaining redox balance after sciatic nerve injury. The study showed that 6 weeks of voluntary wheel running reduces neuropathic pain caused by chronic constriction injury. This reduction was linked to decreased nitrotyrosine immunoreactivity, a marker for peroxynitrite, at the injury site. The study also found that voluntary wheel running increases superoxide scavenging by increasing the expression of superoxide dismutases 1 and 2. The prevention of neuropathic pain was also associated with the activation of nuclear factor E2-related factor 2 (Nrf2), a master transcriptional regulator of the antioxidant response. The protective effects of voluntary wheel running were mediated by Nrf2, as suppression was abolished when Nrf2 activation was blocked during the 6-week running phase.


OMIM:164170


UniProtKB:A0A7D5HQP4


UniProtKB:A0A9L0SH84

The study investigates the role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pathophysiology. The researchers injected CGRP directly into the medial cerebellar nuclei (MN) of C57BL/6J mice and observed behaviors that are indicative of migraine-like symptoms. The results showed that CGRP injection caused light aversion, increased anxiety, tactile hypersensitivity, and spontaneous pain. The effects were more pronounced in female mice. The study suggests that the cerebellum, particularly the MN, might be a site of CGRP action contributing to migraine-like hypersensitivity.


UniProtKB:A0A9L0SH84


UBERON:0002037


UniProtKB:A0A9L0SH84

The study investigates the expression of the neuropeptide calcitonin gene-related peptide (CGRP) and the calcitonin receptor (CTR) in the trigeminal ganglia, a key site in craniofacial pain and migraine. The research found that both CGRP and CTR are expressed in 30-40% of trigeminal ganglia neurons in rats, mice, and humans. The study also found that CGRP and CTR are primarily colocalized in small to medium sized neurons, suggesting that CGRP could act in an autocrine manner through a CTR-based receptor, such as the AMY1 receptor. This suggests that a trigeminal ganglia CTR-based receptor may be activated during migraine and could therefore represent a potential target to develop treatments for craniofacial pain and migraine.


UniProtKB:A0A199V1M4


GO:0061551


PR:000001216

The study investigates the role of spinal CCK1 receptors in somatic pain hypersensitivity caused by temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS). The research found that unilateral anterior crossbite (UAC), a type of TMD, can induce somatic pain hypersensitivity. This hypersensitivity is promoted by the cholecystokinin (CCK) receptor-mediated descending facilitation system through neuron-glia cell signaling cascade. The expression levels of CCK1 receptors, interleukin-18 (IL-18) and IL-18 receptors (IL-18R) were significantly up-regulated in the L4 to L5 spinal dorsal horn at 4 weeks post UAC. The study suggests that CCK1 receptor-dependent descending facilitation may mediate central mechanisms underlying the development of widespread somatic pain via a reciprocal neuron-glial signaling cascade.


PR:000001216


NCBIGene:317756

The study investigates the role of the bile acid receptor TGR5 in chronic bladder conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder syndrome (OAB). The researchers found TGR5 mRNA expression in all layers of the bladder, lumbosacral dorsal root ganglia (DRG), and isolated bladder-innervating DRG neurons in mice. The synthetic TGR5 agonist CCDC directly activated a sub-population of bladder-innervating DRG neurons, which was diminished in Trpv1-/- but not Trpa1-/- DRG neurons. The study also showed that both endogenous and synthetic TGR5 agonists enhanced afferent mechanosensitivity to bladder distension. The enhanced mechanosensitivity induced by CCDC was absent in Gpbar1-/- mice, indicating a role for the TGR5 receptor in mediating bladder afferent hypersensitivity to distension.


NCBIGene:317756


PUBCHEM.COMPOUND:44592018


NCBIGene:317756

Interstitial cystitis/bladder pain syndrome (IC/BPS)


MONDO:0010150

Peripheral sympathetic and sensory nerves

The study investigates the relationship between pain and sympathetic neurotransmission in oral cancer. It was found that human head and neck squamous cell carcinoma (HNSCC) tumors and mouse tumor tissue are innervated by peripheral sympathetic and sensory nerves. β-adrenergic 1 and 2 receptors (β-ARs) are overexpressed in human oral cancer cell lines, and norepinephrine treatment increased β-AR2 protein expression and cancer cell proliferation. The study also found that norepinephrine-treated cancer cell lines secrete more tumor necrosis factor alpha (TNFα), which increases nociceptive behavior. This behavior was reduced during systemic β-adrenergic inhibitory treatment with propranolol. Additionally, chemical sympathectomy using guanethidine led to a significant reduction in tumor size and nociceptive behavior.


UniProtKB:E7QT22


PUBCHEM.COMPOUND:439260


PUBCHEM.COMPOUND:4946

orofacial cancer-induced nociceptive behavior


PUBCHEM.COMPOUND:3518


NCBIGene:2543082

The study identifies a long noncoding RNA (lncRNA), named nerve injury-specific lncRNA (NIS-lncRNA), that is upregulated in dorsal root ganglia (DRGs) in response to nerve injury. This upregulation is triggered by an increase in DRG ELF1, a transcription factor that binds to the NIS-lncRNA promoter. The upregulation of NIS-lncRNA leads to an increase in CCL2 expression, which in turn increases excitability in DRG neurons and produces neuropathic pain symptoms. The study suggests that NIS-lncRNA promotes the binding of the RNA-interacting protein FUS to the Ccl2 promoter, thereby augmenting Ccl2 transcription in injured DRGs. Blocking the upregulation of NIS-lncRNA attenuates nerve injury-induced CCL2 increase and nociceptive hypersensitivity, suggesting that NIS-lncRNA could be a potential target in neuropathic pain management.


NCBIGene:102637887


UniProtKB:A0A0S7ERQ8


UniProtKB:A0A7J7J976


MONDO:0006685

The study investigates the relationship between prenatal hypoxia-ischemia (HI) injury, which can cause cerebral palsy (CP), and changes in spinal nociceptive circuitry. The research was conducted on New Zealand White rabbit kits and found that HI caused an expansion of peptidergic afferents (marked by expression of calcitonin gene-related peptide) in both the superficial and deep dorsal horn. Non-peptidergic nociceptive afferent arborization was unaltered in HI kits, but overlap of the two populations (peptidergic and non-peptidergic nociceptors) was increased by HI. Mechanical and thermal nociception was enhanced in HI kits even in the absence of motor deficits. The findings suggest that prenatal HI injury impacts spinal sensory pathways in addition to the more well-established disruptions to descending motor circuits.


MONDO:0006685


PR:000003237

The study found that the scaffolding protein 14-3-3γ mediates the long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons. This inhibition is a potential barrier for the development of peripherally-restricted KOR agonists that produce analgesia. The protein 14-3-3γ is upregulated in peripheral sensory neurons following activation of c-Jun N-terminal kinase (JNK) with the KOR antagonist norbinaltorphimine (norBNI). Knockdown of 14-3-3γ eliminates the long-term reduction in KOR-mediated cAMP signaling by norBNI in peripheral sensory neurons. Overexpression of 14-3-3γ in KOR expressing CHO cells prevented KOR-mediated inhibition of cAMP signaling.


UniProtKB:A0A3R7MMV8


PUBCHEM.COMPOUND:44326617


PR:000003237

inhibits when overexpressed in KOR expressing CHO cells


UBERON:0001016

The paper discusses the role of interoception in maintaining physiological status and metabolic homeostasis. It highlights that skeletal metabolism is tightly regulated by the nervous system and that skeletal interoception regulates bone homeostasis. The study also discusses the effects of interoception on the skeleton and whole-body metabolism, and its regulation in the context of pathological conditions and skeletal pain.


NCBIGene:490404

The study found that deleting the Tropomyosin Receptor Kinase A (TrkA) in sensory neurons of mice eliminates pain associated with Osteoarthritis (OA). This is achieved through the intervention of Nerve Growth Factor (NGF)/TrkA in peripheral sensitization.


NCBIGene:490404


NCBIGene:58133


EFO:0009510

The study found that peripheral nerve injury sensitizes a complex network of spinal cord dorsal horn neurons, leading to allodynia and neuropathic pain. The neuropeptide Y (NPY) Y1 receptor-expressing interneuron (Y1-IN) population is identified as a potential target for drug development. The study showed that nerve injury enhanced the excitability of Y1-INs and caused allodynia and affective pain. The study also found that chemogenetic inhibition of Y1-INs or intrathecal administration of a Y1-selective agonist reduced allodynia. The deletion of Npy1r in dorsal horn neurons prevented the anti-hyperalgesic effects of the intrathecal Y1 agonist, suggesting that spinal Y1-INs are necessary for the behavioral symptoms of neuropathic pain.


EFO:0009510


UniProtKB:Q5FVH5


PR:000006601

The study investigates the role of clathrin-dependent endocytosis in the sensitization of nociceptors and synaptic transmission in spinal nociceptive circuits, which are involved in chronic pain. The researchers found that mRNA encoding dynamin (Dnm) 1 to 3 and adaptor-associated protein kinase 1 (AAK1), which mediate this endocytosis, were localized to primary sensory neurons in both mice and humans. Inhibiting these proteins reversed symptoms of pain in preclinical models. The study suggests that endocytosis inhibitors could be a potential therapeutic approach for pain treatment.


UniProtKB:P0C1X8

Adaptor-associated protein kinase 1 (AAK1)


PR:000006601


UniProtKB:P0C1X8


NCBIGene:102637887

The study investigates the effect of nerve injury-specific long non-coding RNA (NIS-lncRNA) antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes. The results show that intrathecal injection of NIS-lncRNA antisense oligonucleotides mitigates neuropathic pain without causing cellular toxicity. This is achieved by blocking the increased expression of NIS-lncRNA and C-C chemokine ligand 2 (CCL2) in the dorsal root ganglia (DRG) and reducing hyperactivities of neurons and astrocytes in the spinal cord dorsal horn. The findings suggest potential clinical application of NIS-lncRNA antisense oligonucleotides for neuropathic pain management.


PUBCHEM.COMPOUND:16197676


NCBIGene:102637887


HP:0003323

The study investigates the feasibility and acceptability of a smartphone application with an electronic headache diary and a progressive muscle relaxation (PMR) intervention for people with migraines. The results showed that the app was used frequently and was well-received by the participants. The use of the app was associated with a decrease in migraine disability and an increase in headache-free days. More frequent use of PMR was associated with more headache-free days.


NCBITaxon:78354


HP:0003323


NCBIGene:4988

The study found that a single haplotype, tagged by rs10485058, in the OPRM1 gene's 3' untranslated region was significantly associated with the efficacy of methadone in treating opioid dependence. Patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those with the A/G and G/G genotypes. This genotype also predicted self-reported relapse rates in an independent population of Australian patients of European descent receiving opioid substitution therapy. In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect.


NCBITaxon:489455


PUBCHEM.COMPOUND:16204582


UNII:ZR8P5M7HVX


EFO:0010702

Extended-release injection naltrexone (XR-NTX)

The study investigates the rate of relapse in opioid use disorder patients after short term inpatient treatment and withdrawal from opioids without follow-up medication assisted treatment (MAT). The study found that relapse rates were high across all treatment settings, but were particularly high in short term inpatient treatment. However, the use of extended-release injection naltrexone (XR-NTX) showed a modest protective effect against relapse across all settings.


MESH:D000079522

The study found that cigarette smoking is prevalent among people living with HIV/AIDS who also abuse alcohol and/or illicit substances. The research evaluated whether smoking predicts virologic non-suppression and low CD4 count during a one-year follow-up in medically hospitalized, substance-using people living with HIV/AIDS. The results showed that non-smokers were significantly more likely to achieve viral suppression compared to smokers. There was also a significant smoking-by-time interaction for CD4 cell count, with smokers less likely to have a low CD4 count at baseline and 6-month follow-up, but more likely to have a low CD4 count at 12-month follow-up. This suggests that smoking may affect immunological functioning in HIV-infected substance users.


MESH:D000079522


RXCUI:1551466

The study compared the effectiveness of extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, in preventing opioid relapse. The results showed that it was more difficult to initiate patients on XR-NTX than BUP-NX, which negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. The study suggests that future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.


PUBCHEM.COMPOUND:6321408


RXCUI:1551466


PUBCHEM.COMPOUND:446220

The study analyzed the cognitive profiles of adults seeking treatment for substance use disorders at various community-based facilities. The cognitive performance of five primary substance subgroups (alcohol, cocaine, stimulants, opioids, marijuana) was compared. The study found that half of the total sample showed impairment in cognitive flexibility and reasoning, and over one-third had impairment in verbal learning and memory. Stimulant and cocaine users showed significantly greater clinical impairment in attention and mental control compared to alcohol and opioid users. Cocaine users showed the greatest overall impairment, although these were not statistically different from other subgroups. The study confirmed a high prevalence of significant cognitive dysfunction across all substance use categories among treatment-seeking adults.


MESH:D016578

The study aimed to understand the profile of treatment-seeking crack-dependent individuals in Brazil. The study found that the majority of these individuals were male, unemployed, homeless, and had low levels of education. They had been using crack for an average of 10 years and most had previously sought treatment for their dependence. Many of the participants also had dependence on other substances, with tobacco and alcohol being the most common. The participants also showed significant psychiatric symptoms and impulsivity, with nearly half showing psychotic symptoms, 90% showing depressive symptoms, and 80% showing anxiety symptoms.


MESH:D016578


MESH:D062789


CHEBI:30879


PUBCHEM.COMPOUND:446220

The study investigates factors influencing long-term opioid abstinence in adults with opioid use disorder (OUD) who were treated with either methadone or buprenorphine/naloxone. It was found that 33.2% of the participants achieved 5-year abstinence from heroin, and 20.7% remained abstinent from both heroin and other opioids. Factors positively associated with abstinence included older age at first opioid use, lower impulsivity, longer duration of treatment for OUD, and greater social support. Conversely, cocaine users, injection drug users, Hispanics, and those treated in clinics on the West Coast were less likely to achieve 5-year abstinence.


RXCUI:1551466

The study examined gender differences in patients with opioid use disorder (OUD) who were receiving inpatient services and participating in a trial comparing extended-release naltrexone to buprenorphine. The findings revealed that women were younger, more likely to identify as bisexual, live with a sexual partner, be financially dependent, and less likely to be employed. Women also reported greater psychiatric comorbidity and risk behaviors, and a shorter duration but similar age of onset of opioid use. The study suggests that interventions targeting these disparities should be explored, as women may face complicated treatment initiation, retention, and recovery.


RXCUI:1150288

The study found that the introduction of Oregon's Coordinated Care Organization (CCO) model and Medicaid expansion led to an increase in treatment entry rates for alcohol use disorders from 35% in 2010 to 41% in 2015. The number of Medicaid enrollees diagnosed with an alcohol use disorder increased by about 150% from 10,360 in 2013 to 25,454 in 2014 following Medicaid expansion. The percentage of individuals with an alcohol use disorder who were prescribed medication to support recovery also increased from 2.3% in 2010 to 3.8% in 2015.


PUBCHEM.COMPOUND:5360515

The study compared the effectiveness of extended-release injectable suspension naltrexone (XR-naltrexone) and oral naltrexone, both combined with behavioral therapy, in treating opioid use disorder. The results showed that patients treated with XR-naltrexone had twice the rate of treatment retention at 6 months compared to those treated with oral naltrexone. This suggests that XR-naltrexone combined with behavioral therapy is an effective treatment for patients seeking opioid withdrawal and nonagonist treatment for preventing relapse to opioid use disorder.


PUBCHEM.COMPOUND:44273477


MESH:D062789

The study found that opioid misuse or opioid use disorder (OUD) is more common among tobacco users, particularly those who are male, unemployed, or polydrug users. The data was collected from 2000 adult primary care patients across 5 clinics. Among past-year tobacco users, the prevalence of opioid misuse and OUD was 14.0% and 9.5%, respectively. Three subgroups of tobacco users were identified: a tobacco-minimal drug use group, a tobacco-cannabis use group, and a tobacco-opioid/polydrug use group.


HP:0030157

The study investigates the association between pain catastrophizing and pain-related outcomes in individuals with substance use disorders and chronic pain. Pain catastrophizing refers to the tendency to interpret pain as harmful, intolerable, or uncontrollable. The study found that greater pain catastrophizing was associated with more pain interference, higher levels of craving, more anxiety symptoms, and more days of mood difficulties, adjusted for demographic characteristics and pain severity. This suggests that pain catastrophizing could be a potential therapeutic target to improve substance use treatment outcomes.


HP:0030157


NCIT:C176399

The study investigates the effect of increased regulation of hydrocodone-combination analgesics on opioid prescribing in an urban health care system. The data showed a significant decrease in the probability of providers prescribing hydrocodone-combination prescriptions (HCPs) after the regulation. However, there was a significant increase in the probability of codeine-combination and tramadol prescriptions. Chronic opioid therapy (COT) patients received more opioid prescriptions after the regulation. Despite the decline in HCPs, a third of patients prescribed opioids remained on doses ≥20 MME/day. The study suggests that physicians and health care systems need to reduce their reliance on opioids in treating pain, especially chronic pain.


NCIT:C176399


PUBCHEM.COMPOUND:5284596

The study reviews pharmacists' attitudes towards dispensing naloxone and medications for opioid use disorder (OUD), such as methadone, buprenorphine, and naltrexone. The results show that pharmacists generally agree with a naloxone standing order and believe that naloxone should be dispensed to individuals at risk of an opioid overdose. They also support dispensing buprenorphine. However, some pharmacists expressed negative attitudes. The main barriers to implementation include education and training, workflow, and management support.


PUBCHEM.COMPOUND:4095

The study aimed to identify factors associated with buprenorphine treatment utilization over time in individuals with opioid use disorder (OUD). The study found that approximately 9.3-11.2% of participants utilized buprenorphine treatment over the 2 years of follow-up. The study found that individuals who perceived buprenorphine to be both accessible and acceptable were most likely to use buprenorphine during follow-up. In contrast, individuals who perceived buprenorphine to be unacceptable were least likely to use buprenorphine, regardless of the level of perceived access to the medication. Buprenorphine treatment utilization was also negatively associated with Hispanic ethnicity, West coast context, and cumulative months receiving methadone treatment and incarceration during follow-up.


PUBCHEM.COMPOUND:126961754

The study aimed to understand the frequency and intensity of suicidal motivations and perceived overdose risk among individuals admitted for opioid use disorder detoxification/stabilization. The study found that over half of the participants reported some desire to die prior to their most recent opioid overdose, with 36% reporting a strong desire to die and 21% reporting a definite desire to die. Perceptions of overdose risk were also variable, with 30% reporting no likelihood of overdose and 13% reporting a high likelihood. The study concludes that suicidal motivation prior to opioid overdose is common and falls along a continuum of severity.


EFO:0010702


EFO:0010702

The study reports on the prevalence of opioid use disorder (OUD) and its treatment with buprenorphine among primary care patients in six large health systems in the U.S. The study found that among 1,368,604 primary care patients, 1.0% had documented OUD, and among these, 21.0% had OUD treatment with buprenorphine. The study also found disparities in OUD treatment across demographic and clinical characteristics, with less buprenorphine treatment among those with greater acute care utilization.


PUBCHEM.COMPOUND:135036

The study investigates the factors associated with the initiation of medications for opioid use disorder (MOUD) and alcohol use disorder (MAUD) during hospitalization. The study found that past methadone maintenance treatment, homelessness, and partner substance use were positively associated with MOUD/MAUD initiation. However, concurrent methamphetamine use disorder was negatively associated with MOUD/MAUD initiation. The findings suggest that hospitalization may be an opportunity to reach highly-vulnerable people and emphasize the need for hospital-based addictions care.


EFO:0010702

The study investigated the association between medication treatments for Opioid Use Disorder (OUD) and pain. The study involved a randomized trial of methadone versus buprenorphine/naloxone on 1241 individuals with OUD. The results showed that almost half of the participants reported pain at baseline. However, there was no significant difference in pain improvement between the two treatment arms. Improvement in pain early in treatment was associated with a greater likelihood of retention in treatment.


PUBCHEM.COMPOUND:6321408


EFO:0003843

no significant improvement with treatment


EFO:0003843


EFO:0003843

improvement associated with increased treatment retention


PUBCHEM.COMPOUND:3345

The study investigates the high rates of fentanyl-related overdose deaths in New Hampshire (NH), which are more than three times the national average. The majority of the participants had knowingly used fentanyl, with 70% reporting at least one overdose. Most participants stated that most heroin available in NH was laced with fentanyl, which increased the risk of overdose. Despite acknowledging that fentanyl is the primary cause of overdoses, individuals continue to use it due to high availability and limited access to prevention, treatment, and harm reduction programs. The study suggests that policies targeting innovative prevention, harm reduction, and treatment efforts are needed to address the crisis.


PUBCHEM.COMPOUND:5462328


PUBCHEM.COMPOUND:126961754


MONDO:0024317

The study analyzed electronic health record data from 2013 to 2018 among adults aged ≥18 years in a large academic healthcare system to understand the association of Chronic non-cancer pain (CNCP) with substance use disorder (SUD). The prevalence of CNCP was 46.6% and any SUD was 11.2%. The majority of patients with a SUD had CNCP. The presence of CNCP was associated with more mental health disorders and chronic medical conditions among each SUD group. CNCP was associated with significantly decreased odds of overdose among those with opioid use disorder but increased odds of overdose and healthcare utilization among other SUDs. The direction and magnitude of the association between CNCP and negative health indicators differed as a function of SUD type and gender.


MONDO:0024317


MESH:C069856

The study compared the Timeline Follow-back (TLFB) self-report method and Oral Fluid Testing (OFT) for detecting substance use in adult primary care patients. The substances tested included marijuana, heroin, cocaine, and non-medical use of prescription opioids. The overall concordance rates between TLFB and OFT were 94.9% or higher for each substance. However, marijuana was the only substance with lower detection on OFT than self-report. Cocaine, prescription opioids, and heroin all had higher detection via OFT than TLFB. The study suggests that researchers should consider the implications of using either self-report or oral fluid testing in isolation, depending on the substance and collection setting.


MONDO:0005367

The study examined patterns of substance use among participants newly enrolled in a syringe services program (SSP) in Florida. A three-class solution was found: Heroin-Dominant class (73.9%), Methamphetamine-Dominant class (9.5%) and Heroin/Cocaine class (16.6%). The Heroin/Cocaine class were more likely to report homelessness, sharing works, unprotected sex, public injection, and to be Hepatitis C (HCV) positive. The Methamphetamine-Dominant class were more likely to be male, Hispanic, gay or bisexual orientation, HIV positive, to report unprotected sex and sex with people who inject drugs (PWID). The lowest and highest syringe coverage were among those in the Heroin/Cocaine and Methamphetamine-Dominant classes, respectively. The study suggests that multi-component, targeted preventive interventions and need-based syringe distribution policies are required to further reduce HIV and HCV risk among various PWID populations.


NCBIGene:101080211

The National Drug Abuse Treatment Clinical Trials Network (CTN) has been utilizing digital technologies to better understand and treat substance use disorders (SUDs). This includes the use of digital screeners for SUDs in general medical settings, a multi-site clinical trial that led to the first "prescription digital therapeutic" authorized by the FDA for SUD treatment, the use of telehealth for SUD treatment in rural and under-resourced communities, and the detection of cocaine-taking behavior via smartwatch sensing. The CTN has also conducted clinical trials entirely online and is working on identifying digital biomarkers and understanding the clinical trajectories of individuals receiving medications for opioid use disorder (OUD).


RXCUI:240725

The study investigates the readiness of emergency department (ED) clinicians to initiate buprenorphine treatment for opioid use disorder (OUD). The findings suggest that only a small percentage of clinicians are ready to initiate such treatment. Barriers to readiness include lack of training and experience, concerns about ongoing care, and competing needs for ED resources. Facilitators include education and training, development of local protocols, and feedback on patient experiences and care quality gaps.


PUBCHEM.COMPOUND:11811155


RXCUI:1551466

The study examined the differences in clinical characteristics between emerging adults (≤25 years) and older adults (26+ years) with opioid use disorder (OUD). It was found that the differences were similar across genders. However, women aged 26+ years reported more mental health problems compared to women aged ≤25, while men aged ≤25 years reported more mental health problems compared to men aged 26+ years. The study suggests that different strategies for OUD treatment may be necessary to address psychiatric comorbidities that differ across genders.


MONDO:0002009

The study found that a lifetime diagnosis of major depressive disorder was the best predictor of successful opioid use outcome in the Prescription Opioid Addiction Treatment Study (POATS). The study also found that while depressive symptoms decreased significantly throughout treatment, this improvement was not associated with opioid outcomes. Reporting a goal of opioid abstinence at treatment entry was also not associated with outcomes. However, mutual-help group participation was associated with good treatment outcomes. Despite these findings, a history of depression remained associated with good opioid outcomes.


NCIT:C55447

improvement not associated with use outcome


PUBCHEM.COMPOUND:6321408


MONDO:0002009


MESH:C088247

The study examined the effects of initiating antiretroviral therapy (ART) in the hospital for persons living with HIV and substance use disorder (SUD). It was found that initiating ART in the hospital was associated with increased linkage to HIV care and frequency of outpatient care visits at 6 and 12 months. However, there was no association between hospital ART initiation and retention and viral suppression over a 12-month period. The study suggests that starting ART in the hospital is beneficial for increasing linkage to HIV care and frequency of visits for PLWH and SUD.


EFO:0010702

The study investigates the prevalence of multiple drug use disorders (DUDs) among inpatient hospitalizations in the United States. Data from the 2016 National Inpatient Sample showed that approximately 50.1% of drug-involved hospitalizations had multiple DUD diagnoses. Opioid use disorder accounted for 58.6% of these hospitalizations, with 51.2% of these having multiple DUD diagnoses. The most common secondary DUD diagnoses among opioid-involved hospitalizations were cocaine, cannabis, and sedatives. Factors such as being aged 18-25 years, living in low-income areas, and having a secondary diagnosis of mental disorders or tobacco/alcohol use disorder were associated with increased odds of having multiple DUD diagnoses.


RXCUI:378762

The study compared the effectiveness of extended-release naltrexone (XR-NTX) and sublingual buprenorphine-naloxone (BUP-NX) in treating opioid use disorder (OUD) among Black adults. The results showed no significant preference for either treatment. However, only 59.5% of those assigned to XR-NTX successfully started the medication compared to 91.6% for BUP-NX. No significant differences were found in treatment retention or relapse rates between the two groups. Despite a significant initiation hurdle with XR-NTX, both medications were similar in effectiveness once started, but dropout rates were high.


ZFIN:ZDB-GENE-090416-1

The study aimed to predict the occurrence of opioid use disorder (OUD) in 25-year-olds based on data collected when they were 16. The researchers used two measures: the transmissible liability index (TLI), which measures heritable risk, and the consumption frequency index (CFI), which documents substance use events. The study found that the TLI and CFI at 16 years of age could predict OUD at 25 years with 86% accuracy. These measures also mediated the association between parental substance use disorder and OUD in offspring, indicating their effectiveness in evaluating risk and prodrome.


MONDO:0100096

The paper discusses the effectiveness of Medications for Opioid Use Disorder (MOUD), such as methadone and buprenorphine, in treating Opioid Use Disorder (OUD) and reducing overdose risk. However, the treatment rates remain low in the US, and access to such treatments is becoming increasingly difficult due to the COVID-19 pandemic. The paper suggests that community pharmacies could be a solution to this problem, as they have been in Canada, Australia, and Europe. However, US pharmacists are currently not allowed to prescribe MOUD and can only dispense methadone for pain treatment, not OUD. The paper calls for policy changes to allow US pharmacists to prescribe and dispense MOUD.