Model Of Chronic Pain Research Articles

Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment.

Memory impairment in chronic pain patients is substantial and common, and few therapeutic strategies are available. Chronic pain-related memory impairment has susceptible and unsusceptible features. Therefore, exploring the underlying mechanisms of its vulnerability is essential for developing effective treatments. Here, combining two spatial memory tests (Y-maze test and Morris water maze), we segregated chronic pain mice into memory impairment-susceptible and -unsusceptible subpopulations in a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. RNA-Seq analysis and gain/loss-of-function study revealed that S1P/S1PR1 signaling is a determinant for vulnerability to chronic pain-related memory impairment. Knockdown of the S1PR1 in the dentate gyrus (DG) promoted a susceptible phenotype and led to structural plasticity changes of reduced excitatory synapse formation and abnormal spine morphology as observed in susceptible mice, while overexpression of the S1PR1 and pharmacological administration of S1PR1 agonist in the DG promoted an unsusceptible phenotype and prevented the occurrence of memory impairment, and rescued the morphological abnormality. Finally, the Gene Ontology (GO) enrichment analysis and biochemical evidence indicated that downregulation of S1PR1 in susceptible mice may impair DG structural plasticity via interaction with actin cytoskeleton rearrangement-related signaling pathways including Itga2 and its downstream Rac1/Cdc42 signaling and Arp2/3 cascade. These results reveal a novel mechanism and provide a promising preventive and therapeutic molecular target for vulnerability to chronic pain-related memory impairment.

Epidural injection of varying doses of capsaicin alleviates inflammatory pain in rats via the TLR4/AKT/NF-κB pathway.

Capsaicin (CAP) induces transient pain sensation by activating transient receptor potential vanilloid-1 (TRPV1). However, the initial neuronal excitation induced by CAP is followed by a prolonged refractory period, resulting in long-lasting analgesia. Although the effects of CAP on microglia in the dorsal root ganglion of neuropathic pain disorders have been reported, the regulatory pathways of CAP on microglia remain poorly defined. A chronic pain model was established via plantar injection of complete Freund's adjuvant (CFA), and different doses of CAP were administered to rats. Pain behavior, expression of pain-related factors, protein expression of TRPV1 in nerve cells, and the inflammatory activation of microglia were evaluated. In vitro experiments were conducted to explore the activation and migration ability of microglia, expression of inflammatory cytokines and pathway proteins, TRPV1 expression in nerve cells, and intracellular calcium concentration under different doses of CAP. Different doses of CAP alleviated chronic pain in rats, reduced TRPV1 expression in nerve cells, and inhibited the activation of microglia; however, high doses of CAP were particularly effective in improving chronic pain. In vitro experiments confirmed that CAP reduces the secretion of inflammatory cytokines by microglia via inhibition of the TLR4/AKT/NF-κB signaling pathway. This mechanism reduced the injury and apoptosis of nerve cells, the expression of TRPV1, and the influx of calcium ions in nerve cells. CAP reduced inflammatory responses in microglia in a dose-dependent manner by inhibiting the TLR4/AKT/NF-κB signaling pathway, which consequently reduced TRPV1 expression on neuronal cells and reduced chronic pain.

Pregabalin produces analgesia in males but not females in an animal model of chronic widespread muscle pain.

Pregabalin, which acts on the α2δ-1 subunit of voltage-gated calcium channels, relieves ≥50% of pain in a third of individuals with fibromyalgia. Thus far, preclinical studies of pregabalin have predominantly used male animals. The purpose of our study was to investigate potential sex differences in the analgesic efficacy of pregabalin that may contribute to disparities in human outcomes. We used a mouse model of chronic widespread muscle pain (CWP) to test the effects of pregabalin on muscle hyperalgesia, nonreflexive pain, and motor behaviors. The CWP pain model combines 2 pH 4.0 saline injections, spaced 5 days apart, into the gastrocnemius muscle and produces bilateral muscle hyperalgesia. Furthermore, we explored sex differences in the mRNA and protein expression of the α2δ-1 subunit of voltage-gated calcium channels in the dorsal horn of the spinal cord and dorsal root ganglia after development of CWP. Pregabalin fully attenuated muscle hyperalgesia bilaterally in male but not female mice with equal motor deficits produced in both sexes. In addition, using the conditioned place preference test, mice of both sexes with CWP spent significantly more time in the pregabalin-paired chamber compared with baseline, but not significantly greater than pain-free controls. Chronic widespread muscle pain produced no changes in α2δ-1 subunit mRNA or protein expression in the dorsal horn of the spinal cord or dorsal root ganglia in either sex. Overall, these findings indicate pregabalin may be more effective in treating CWP in males, but the factors leading to these differences are not fully understood.

Astrocyte neuronal metabolic coupling in the anterior cingulate cortex of mice with inflammatory pain.

Chronic pain is a major global concern, with at least 1 in 5 people suffering from chronic pain worldwide. Mounting evidence indicates that neuroplasticity of the anterior cingulate cortex (ACC) is a critical step in the development of chronic pain. Previously, we found that chronic pain and fear learning are both associated with enhanced neuronal excitability and cause similar neuroplasticity-related gene expression changes in the ACC of male mice. However, neuroplasticity, imposes large metabolic demands. In the brain, neurons have the highest energy needs and interact with astrocytes, which extract glucose from blood, mobilize glycogen, and release lactate in response to neuronal activity. Here, we use chronic and continuous inflammatory pain models in female and male mice to investigate the involvement of astrocyte-neuronal lactate shuttling (ANLS) in the ACC of female and male mice experiencing inflammatory pain. We found that ANLS in the mouse ACC promotes the development of chronic inflammatory pain, and expresses sex specific patterns of activation. Specifically, whereas both male and female mice show similar levels of chronic pain hypersensitivity, only male mice show sustained increases in lactate levels. Accordingly, chronic pain alters the expression levels of proteins involved in lactate metabolism and shuttling in a sexually dimorphic manner. We found that disrupting astrocyte-neuronal lactate shuttling in the ACC prior to inflammatory injury prevents the development of pain hypersensitivity in female and male mice, but only reduces temporary pain in male mice. Furthermore, using a transgenic mouse model (itga1-null mice) that displays a naturally occurring form of spontaneous osteoarthritis (OA), a painful inflammatory pain condition, we found that whereas both female and male mice develop OA, only male mice show increases in mechanisms involved in astrocyte-neuronal lactate shuttling. Our findings thus indicate that there are sex differences in astrocyte-neuronal metabolic coupling in the mouse ACC during chronic pain development.

Benzylpiperidine derivatives as new dual μ-opioid and σ1 receptor ligands with potent antinociceptive effects

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σ1R) ligands have displayed promise in exerting robust antinociceptive effects while reducing opioid-related side effects. To discover safer and more effective analgesics, we designed, prepared, and evaluated 30 benzylpiperidine derivatives as dual MOR and σ1R ligands. The obtained benzylpiperidine analogs were tested for MOR and σ1R binding affinity in vitro. The best compound 52 showed high affinity for both MOR [Ki (MOR) = 56.4 nM] and σ1R [Ki (σ1R) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED50 = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED50 = 6.88 mg/kg in mice), formalin test (ED50 = 13.98 mg/kg in rats) and complete Freund’s adjuvant (CFA)-induced chronic pain model (ED50 = 7.62 mg/kg in mice). Moreover, 52 had less MOR-related adverse effects than oxycodone, including constipation, acute hyperlocomotion and physical dependence. The above results suggested that 52 may be a promising candidate for the development of safer analgesics.

PDGFR-α Mediated the Neuroinflammation and Autophagy via the JAK2/STAT3 Signaling Pathway Contributing to Depression-Like Behaviors in Myofascial Pain Syndrome Rats.

Depression often occurs in patients with additional co-morbidities, particularly in cases of chronic pain. Currently, there is a lack of research on the molecular mechanisms of depression under chronic pain conditions and suitable animal models. Due to the contradiction exhibited by platelet-derived growth factor receptor (PDGF/PDGFR) in neuroprotection, further investigation is required. In the present study, we investigated the roles of PDGFR-α in the hippocampus based on rat models of chronic pain (myofascial pain syndrome, MPS) that exhibited depressive phenotypes. The depression-like phenotypes were assessed by the sucrose preference test, forced swimming test, tail suspension test, and the levels of BDNF and 5HT1AR. Electron microscopic analysis and altered expression of autophagy-related proteins revealed reduced autophagy levels in the hippocampus of MPS rats. Phosphorylation PDGFR-α was significantly upregulated in the MPS rat model of depression, as well as the levels of inflammatory factors and p-JAK2/p-STAT3. Treatment with inhibitors of PDGFR-α or JAK2/STAT3 alleviated depressive behaviors, Nissl bodies staining, increased the protein levels of BDNF and 5HT1AR, and decreased the levels of inflammatory factors in MPS rats. Additionally, it restored autophagy levels. These results indicate that PDGFR-α induces neuroinflammation, altered autophagy, and depressive behavior, potentially mediated by the JAK2/STAT3 signaling pathway in MPS rats. PDGFR-α may thus represent a promising therapeutic target for the treatment of this type of depression.

Solvent-mediated analgesia via the suppression of water permeation through TRPV1 ion channels.

Activation of the ion channel transient receptor potential vanilloid 1 (TRPV1), which is integral to pain perception, leads to an expansion of channel width, facilitating the passage of cations and large organic molecules. However, the permeability of TRPV1 channels to water remains uncertain, owing to a lack of suitable tools to study water dynamics. Here, using upconversion nanophosphors to discriminate between H2O and D2O, by monitoring water permeability across activated TRPV1 at the single-cell and single-molecule levels, and by combining single-channel current measurements with molecular dynamics simulations, we show that water molecules flow through TRPV1 and reveal a direct connection between water migration, cation flow and TRPV1 functionality. We also show in mouse models of acute or chronic inflammatory pain that the administration of deuterated water suppresses TRPV1 activity, interrupts the transmission of pain signals and mitigates pain without impacting other neurological responses. Solvent-mediated analgesia may inspire alternative options for pain management.

Oxytocin Analogues for the Oral Treatment of Abdominal Pain.

Abdominal pain presents an onerous reality for millions of people affected by gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The oxytocin receptor (OTR) has emerged as a new analgesic drug target with OTR expression upregulated on colon-innervating nociceptors in chronic visceral hypersensitivity states, accessible via luminal delivery. However, the low gastrointestinal stability of OTR's endogenous peptide ligand oxytocin (OT) is a bottleneck for therapeutic development. Here, we report the development of potent and fully gut-stable OT analogues, laying the foundation for a new area of oral gut-specific peptide therapeutics. Ligand optimisation guided by structure-gut-stability-activity relationships yielded highly stable analogues (t1/2>24 h, compared to t1/2<10 min of OT in intestinal fluid) equipotent to OT (~3 nM) and with enhanced OTR selectivity. Intra-colonic administration of the lead ligand significantly reduced colonic mechanical hypersensitivity in a concentration-dependent manner in a mouse model of chronic abdominal pain. Moreover, oral administration of the lead ligand also displayed significant analgesia in this abdominal pain mouse model. The generated ligands and employed strategies could pave the way to a new class of oral gut-specific peptides to study and combat chronic gastrointestinal disorders, an area with substantial unmet medical needs.

FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia

Navigating the duality of opioids’ potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model. We found that chronic morphine treatment increases FLT3 and MOR co-expression, and that inhibiting FLT3 represses MOR-induced hyperactivation of the cyclic adenosine monophosphate (cAMP) signaling pathway, mitigating maladaptive excitatory processes engaged after chronic morphine treatment. Furthermore, in postsurgical or inflammatory models of chronic pain, co-administering morphine with a FLT3-specific inhibitor not only prevents or suppresses tolerance and hyperalgesia but also potentiates the analgesic efficacy of morphine, without aggravating other morphine-induced adverse effects. Our findings suggest that pairing morphine with FLT3 inhibitors could become a promising avenue for chronic pain management to safely harness the power of opioids, without the risk of dose escalation. By enhancing morphine analgesic potency through FLT3 inhibition, this approach could minimize opioid dosage, thereby curtailing the risk of addiction and other opioid-related side effects.

Enhancing orofacial pain relief: α-phellandrene complexed with hydroxypropyl-β-cyclodextrin mitigates orofacial nociception in rodents.

Orofacial pain affects 10-15% of adults and can severely impact quality of life. Despite ongoing treatment challenges, monoterpene alpha-phellandrene (PHE) shows potential therapeutic benefits. This study aimed to develop and evaluate an inclusion complex of PHE with hydroxypropyl-beta-cyclodextrin (PHE-HPβCD) for treating orofacial pain. The PHE-HPβCD complex was created using physical mixing and characterized by differential scanning calorimetry (DSC) and high-performance liquid chromatography (HPLC) to determine encapsulation efficiency. The complex exhibited a 70.45% encapsulation efficiency. Male Swiss mice were used in models of orofacial pain induced by formalin, cinnamaldehyde, glutamate, and corneal nociception by hypertonic saline. Additionally, cytokine levels (TNF-α and IL-1β) were measured in the upper lip tissue of mice subjected to the formalin model. Both PHE and PHE-HPβCD showed significant antinociceptive effects at a 50mg/kg dose during formalin-induced pain, reducing both neurogenic and inflammatory phases of pain. PHE-HPβCD also reduced TNF-α and IL-1β levels. For cinnamaldehyde and glutamate-induced nociception, both treatments reduced pain behavior, but only PHE-HPβCD decreased eye wipes in corneal nociception. These results suggest that PHE, especially in complexed form, alleviates orofacial pain by potentially modulating pain-related receptors (TRPA1 and TRPV1), mediators, like glutamate, and reducing pro-inflammatory cytokines. Further research is needed to explore the precise mechanisms of PHE in chronic orofacial pain models, but the study indicates promising avenues for new pain treatments.

Drug developmental strategies based on functional analysis of pain-regulating molecules in astrocytes under chronic pain

Spinal cord astrocytes are activated in chronic pain models, especially under conditions of prolonged pain. Hence, targeting spinal cord astrocytes for the development of useful analgesics has attracted much attention. In the CNS, connexin43 (Cx43), a membrane protein expressed and functioning exclusively in astrocytes, is well known to be involved in intercellular signaling as a component of gap junction, but also interacts with intracellular molecules via its characteristically long C-terminal region, thereby affecting cellular function. Previously, we found that Cx43 expression was markedly reduced in spinal dorsal horn astrocytes from a mouse model of neuropathic pain. In order to investigate the relationship between reduced Cx43 expression in spinal astrocytes and the onset of pain, we showed that reduced Cx43 expression altered the expression of pain-related molecules such as the glutamate transporter GLT-1 and the pro-inflammatory cytokine interleukin-6 (IL-6). In particular, we focused on the regulation of IL-6 expression by reduced Cx43 expression in both in vivo and in vitro analyses, and found that IL-6 expression is increased through the Akt- glycogen synthase kinase-3β (GSK-3β) signaling system driven by reduced Cx43 expression during neuropathic pain, which in turn triggers pain. These findings suggest that astrocyte Cx43 is involved in pain prolongation by regulating gene expression of nociceptive factors through interactions with intracellular signaling molecules, which is different from its previously known function, and thus raises expectations for its potential as a new drug target for chronic pain.

GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation

Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1, as well as a GLP-1R antagonist, exendin 9–39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9–39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, exendin 9–39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund’s adjuvant (CFA) and spared nerve injury (SNI), in mice without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9–39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9–39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among the exendin 9–39 fragments, exendin 20–29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20–29 as a promising therapeutic candidate.

Elucidation on the In Vivo Activity of the Bivalent Opioid Peptide MACE2 against Several Types of Chronic Pain.

Biphalin is a bivalent μ/δ opioid receptor agonist showing a promising therapeutic profile with reduced side effects, but as a peptide is limited by poor metabolic stability and blood-brain barrier penetration. To improve these features, we developed the ligand MACE2 and showed initial in vivo efficacy. To further explore the druggability of this ligand, in this report, we tested MACE2 metabolic stability in human plasma, receptor engagement by 3 different routes of administration using the tail-flick test, and MACE2 efficacy in 2 different pathological and chronic pain models. We found that MACE2 had high stability in plasma and could produce target engagement and a tail flick response. We also showed that MACE2 had high analgesic efficacy in CIPN but no efficacy in paw incision. Together, these findings suggest that MACE2 has improved metabolic stability and brain penetration in vivo, prompting further development in clinical testing.

MODULATION OF MORPHINE ANTINOCICEPTIVE AND REWARDING EFFECT BY MIRTAZAPINE IN AN ANIMAL MODEL OF OSTEOARTHRITIC PAIN

People with chronic pain mitigate their suffering by the action of opioids. Adverse reactions aside, opioids are not exempt from potential complications like addiction and abuse, which have posed a global public health problem lately. Finding new therapeutic strategies to improve analgesia and to reduce opioid side effects has become a priority. In this regard, the association of different adjuvant therapies has been postulated. Despite preclinical and clinical evidence supporting the use of antidepressants as analgesics, it is not clear whether they could help reduce the risk of addiction in combination with opioids. To further explore this idea a model of chronic osteoarthritis pain was employed, and a combination of mirtazapine and morphine was used in a chronic regimen in male and female rats. The effects on the development of tactile allodynia, movement-evoked pain, reward, analgesic tolerance, naloxone-induced withdrawal symptoms, impaired locomotor activity and anxiety were evaluated under a 25-day experimental protocol. Additionally, protein expression of μ-opioid receptors and clusterin (related with substance abuse) was evaluated in plasma and in brain structures of the reward system. Chronic morphine caused analgesic tolerance, reward and naloxone-induced withdrawal symptoms. The combination reduced the analgesic tolerance and prevented the development of withdrawal symptoms but showed sex-based differences regarding reward. Increased levels of clusterin in plasma were observed in females treated with morphine, but not with combined therapy. The combination of mirtazapine and morphine could be a promising strategy to improve the management of long-term opioid treatment and its risk of abuse, especially in females.

A long chain fatty acid receptor signaling as a new therapeutic target for stress-induced chronic pain

Psychological and social stresses are known to be risk factors for psychiatric disorders, including depression and anxiety. On the other hand, exposure to these stresses can also cause prolonged and severe pain. However, the pathological mechanism for stress-induced chronic pain is complex, and there are many unresolved aspects, and no effective therapeutic drugs have been established. Since the discovery of the long-chain fatty acid receptor GPR40/FFAR1 about 20 years ago, research on the mechanism that promotes insulin secretion in the pancreas has progressed. Previously, we have worked to elucidate the physiological effects of GPR40/FFAR1 in the central nervous system and has found that it is involved in the regulation of pain and emotion. Based on these findings, they are now investigating the involvement of fatty acid receptors signaling in the development of stress-related chronic pain. In this review, we discuss the status of psychological stress-related chronic pain and the GPR40/FFAR1-mediated and -striking regulatory mechanisms of stress-induced chronic pain, based on our findings using a mouse model of chronic pain created by loading postoperative pain to a social defeat stress model mouse that mimics psychosocial stress. We summarized about the involvement of fatty acid receptor signaling as a new therapeutic candidate for chronic pain in this review.

Discordance between preclinical and clinical testing of NaV1.7-selective inhibitors for pain.

The voltage-gated sodium channel NaV1.7 plays an important role in pain processing according to genetic data. Those data made NaV1.7 a popular drug target, especially since its relatively selective expression in nociceptors promised pain relief without the adverse effects associated with broader sodium channel blockade. Despite encouraging preclinical data in rodents, NaV1.7-selective inhibitors have not yet proven effective in clinical trials. Discrepancies between preclinical and clinical results should raise alarms. We reviewed preclinical and clinical reports on the analgesic efficacy of NaV1.7-selective inhibitors and found critical differences in several factors. Putting aside species differences, most preclinical studies tested young male rodents with limited genetic variability, inconsistent with the clinical population. Inflammatory pain was the most common preclinical chronic pain model whereas nearly all clinical trials focused on neuropathic pain despite some evidence suggesting NaV1.7 channels are not essential for neuropathic pain. Preclinical studies almost exclusively measured evoked pain whereas most clinical trials assessed average pain intensity without distinguishing between evoked and spontaneous pain. Nearly all preclinical studies gave a single dose of drug unlike the repeat dosing used clinically, thus precluding preclinical data from demonstrating whether tolerance or other slow processes occur. In summary, preclinical testing of NaV1.7-selective inhibitors aligned poorly with clinical testing. Beyond issues that have already garnered widespread attention in the pain literature, our results highlight the treatment regimen and choice of pain model as areas for improvement.

Related Factors and Risk Prediction of Chronic Pain after Knee Replacement.

This study aimed to explore potential risk factors associated with chronic pain after total knee arthroplasty (TKA) and to establish the risk prediction model of chronic postoperative pain (CPSP). This study retrospectively analyzed the clinical data of 160 patients who underwent TKA in our hospital between January 2021 and January 2024. Relevant data such as the baseline characteristics, past medical history, CPSP condition, and pain numerical rating scale (NRS) were retrieved from the medical information system. Logistic regression analysis was performed on the risk factors affecting the postoperative CPSP of the patients. The identified risk factors were incorporated to develop a risk-prediction model. Among the 160 patients, 67 (41.88%) had CPSP at or around the operation incision. The NRS pain score was significantly higher in the CPSP group than in the non-CPSP group during exercise preoperative and 3 months post-operation. Furthermore, the CPSP group had a higher NRS score than the non-CPSP group at rest 3 months after the procedure (p < 0.05). We observed that the preoperative NRS score, preoperative hospital for special surgery (HSS) score, postoperative functional training, and postoperative adverse events were the independent factors influencing the occurrence of CPSP after TKA (p < 0.05). Additionally, there was a significant positive correlation between preoperative NRS score, postoperative adverse events, and CPSP pain severity, and a significant negative correlation between preoperative HSS score, postoperative functional training, and CPSP pain severity (p < 0.05). The receiver operating characteristic (ROC) curve had excellent calibration and prediction capabilities for the predictive model of CPSP after TKA, with the area under the curve (AUC) of 0.868 (95% CI: 0.811-0.925). In this study, the predictive model of CPSP risk for patients after TKA surgery was initially constructed, which can help medical staff predict the risk of CPSP in patients after surgery individually, thereby preventing the occurrence of CPSP.

Neuropeptide Y Y2 receptors in acute and chronic pain and itch

Pain and itch are regulated by a diverse array of neuropeptides and their receptors in superficial laminae of the spinal cord dorsal horn (DH). Neuropeptide Y (NPY) is normally expressed on DH neurons but not sensory neurons. By contrast, the Npy2r receptor (Y2) is expressed on the central and peripheral terminals of sensory neurons but not on DH neurons. Neurophysiological slice recordings indicate that Y2-selective agonists inhibits spinal neurotransmitter release from sensory neurons. However, behavioral pharmacology studies indicate that Y2 agonists exert minimal changes in nociception, even after injury. Additional discrepancies in the behavioral actions of the Y2-antagonist BIIE0246 – reports of either pronociception or antinociception – have now been resolved. In the normal state, spinally-directed (intrathecal) administration of BIIE0246 elicits ongoing nociception, hypersensitivity to sensory stimulation, and aversion. Conversely, in the setting of nerve injury and inflammation, intrathecal BIIE024 reduced not only mechanical and thermal hypersensitivity, but also a measure of the affective dimension of pain (conditioned place preference). When administered in chronic pain models of latent sensitization, BIIE0246 produced a profound reinstatement of pain-like behaviors. We propose that tissue or nerve injury induces a G protein switch in the action of NPY-Y2 signaling from antinociception in the naïve state to the inhibition of mechanical and heat hyperalgesia in the injured state, and then a switch back to antinociception to keep LS in a state of remission. This model clarifies the pharmacotherapeutic potential of Y2 research, pointing to the development of a new non-opioid pharmacotherapy for chronic pain using Y2 antagonists in patients who do not develop LS.

Identification of texture MRI brain abnormalities on Fibromyalgia syndrome using interpretable machine learning models

To provide objective diagnostic markers for fibromyalgia symptoms (FMS) diagnosis, we have created interpretable extreme gradient boosting (XGBoost) models using radiomics to aid in the diagnosis of chronic pain (CP) and to develop nomogram models for diagnosing subgroups of FMS. A group of 54 patients with CP and 71 healthy controls was randomly separated into training and validation groups, using a 7:3 ratio. Radiomics features were extracted from grey-matter and white-matter in the filtered mwp0* image. The Mann-Whitney U test, Spearman’s rank correlation test, and least absolute shrinkage and selection operator (LASSO) were utilized to select features. An XGBoost model was created based on these features, and Shapley Additive exPlanations (SHAP) was used for personalization and visual interpretation. A nomogram was developed for the diagnosis of FMS subgroups, utilizing radiomics scores and clinical predictors. The efficacy of the nomogram was evaluated using the area under the receiver operating characteristic curve, while decision curve analysis was employed to evaluate its clinical efficacy. The XGBoost model displays stability in the training validation group, indicating lower overfitting of CP model. The nomogram model combined with the rad-score has a greater ability to distinguish between typical and sub-clinical than the clinical factor model alone. We developed and validated a CP diagnosis model by XGBoost and realized model visualization through SHAP. The rad-score obtained by machine learning was used to build a nomogram model that combines clinical scales to distinguish patients with typical and sub-clinical fibromyalgia.

Development of Tetrahydroquinoline-Based Inhibitors for Chronic Pain.

Chronic pain affects a substantial portion of the population, posing a significant health challenge. Current treatments often come with limitations and side effects, necessitating novel therapeutic approaches. Our study focuses on disrupting the Cav3.2-USP5 interaction as a strategy for chronic pain management. Through structure-activity relationship studies of a tetrahydroquinoline (THQ) scaffold, we identified a family of lead molecules that demonstrated potent inhibition of the Cav3.2-USP5 interaction. In vitro pharmacokinetic assessments and in vivo studies support the efficacy and drug-like properties of the lead compounds in mouse models of acute and chronic pain. Dependence on the Cav3.2 channels was validated in Cav3.2 null mice, consistent with the proposed mode of action of these small molecules. These findings provide a novel chronic pain treatment strategy, highlighting the potential of these small molecules for further development.