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Chronic neuropathic pain is an increasingly prevalent societal issue that responds poorly to existing therapeutic strategies. The α9α10 nicotinic acetylcholine receptor (nAChR) has emerged as a potential target to treat neuropathic pain. However, challenges in expressing functional α9α10 nAChRs in mammalian cell lines have slowed the discovery of α9α10 ligands and studies into the relationship between α9α10 nAChRs and neuropathic pain. Here, we develop a cell line in the HEK293 background that stably expresses functional α9α10 nAChRs. By also developing cell lines expressing only α9 and α10 subunits, we identify distinct receptor pharmacology between homomeric α9 or α10 and heteromeric α9α10 nAChRs. Moreover, we demonstrate that incubation with nAChR ligands differentially regulates the expression of α9- or α10-containing nAChRs, suggesting a possible mechanism by which ligands may modify receptor composition and trafficking in α9- and α10-expressing cells. We then apply our α9α10 cell line in a screen of FDA-approved and investigational drugs to identify α9α10 ligands that provide new tools to probe α9α10 nAChR function. We demonstrate that one compound from this screen, diphenidol, possesses antinociceptive activity in a murine model of neuropathic pain. These results expand our understanding of α9α10 receptor pharmacology and provide new starting points for developing efficacious neuropathic pain treatments.

The present study examines the possible inhibitory effect of JM-20, a multi-target neuroprotective compound, on the development of morphine-induced hyperalgesia in Male Sprague-Dawley naïve rats. Additionally, the impact of JM-20 on chronic constriction injury (CCI) rats under chronic morphine exposure was investigated, and its efficacy in reducing mechanical hypersensitivity and histopathological changes in the sciatic nerve was assessed. JM-20 (20 mg/kg, per os [p.o.]), administered 60 min before morphine (10 mg/kg, s.c. twice daily at 12 h intervals) for ten days, significantly inhibited the development of morphine-induced hyperalgesia assessed using an electronic pressure-meter paw test, hot-plate, and formalin test, as well as the appearance of spontaneous withdrawal somatic symptoms in rats. Furthermore, JM-20 decreases spinal pro-inflammatory interleukin-1β and restores glutathione to close physiological concentrations, biomarkers directly related to the intensity of mechanical hypernociception. After CCI and sham surgery, co-treatment with JM-20 (10 mg/kg, p.o.) for five days decreased morphine increased-mechanical hypersensitivity, even 12 days after its discontinuation. Continued morphine treatment imposed a neuroinflammatory challenge in CCI animals, further increasing cellularity (>75% immune cell infiltration) with lymphocytes and macrophages. However, JM-20 co-treatment still reduced the presence of cellular infiltrates (51-75%) with a predominance of lymphocytes. Even in the absence of nerve injury, JM-20 attenuated the peripheral neuroinflammatory response observed in morphine-treated sham-operated animals (0% vs. 1-25%). These findings suggest that JM-20 could prevent morphine-induced hyperalgesia by anti-inflammatory and antioxidant mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Fermented milk and palm wine are regularly used by several ethnic groups in Cameroon in traditional treatment rituals for infections, inflammatory, cardiovascular disorders, and even metabolic diseases such as diabetes, hypercholesterolemia etc. Reports from many studies have demonstrated that fermented milk and palm wine are potential sources of probiotic bacteria. However, the capacity of probiotics isolated from these natural sources to alleviate neuropathic pain has not been experimentally tested., Aim of the Study: This study aimed at investigating the ameliorative potential of lactic acid bacteria isolated from palm wine and traditional fermented cow milk on the chronic constriction injury (CCI) induced neuropathic pain in mice., Materials and Methods: Pour plating technique on De Man Rogasa (MRS) agar was utilised for isolation of lactic acid bacteria from fermented cow milk and palm wine, and identified using the 16S r RNA gene sequencing. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve. These bacteria were orally administered at different concentrations to Balb/c mice by gavage for 14 consecutive days. Cold allodynia, mechanical hyperalgesia and exploratory behaviour were evaluated on day 0, 7th and 14th respectively. The total level of calcium, oxidative stress markers and myeloperoxidase were also quantified in the sciatic nerve homogenate. Cyclooxygenase-2(COX-2) and cytokine profile were determined from serum., Results: Lactic acid bacteria were isolated from fermented cow milk and palm wine and two isolates were chosen according to their probiotic potentials and identified as strain of Limolactobacillus fermentum and Enterococcus lactis. Their 16 S rRNA gene sequences were deposited in NCBI genbank with accession number of OP896078 and OR619545, respectively. Pretreatment with Limosilactobacillus fermentum and Enterococcus lactis significantly alleviated mechanical hyperalgesia and cold allodynia with similar effect to the reference drug, morphine. These two isolates ameliorated CCI induced neuropathic pain by increasing antioxida776nts (GSH, CAT and SOD, P < 0.01) and decreasing pro-oxidants (MDA and NO, P < 0.01). Also, they inhibited the release of proinflammatory cytokines (IL-1β, TNF-α, IFN-γ, and IL-6; P < 0.01) and IL-10 level was significantly (P < 0.01) increased when compared to the negative control. Treatment with these bacteria significantly dropped the level of total calcium (P < 0.01), COX-2 (P < 0.01) and MPO (P < 0.01) when compared with the negative control., Conclusion: The neuroprotective potentials of these selected lactic acid bacteria against CCI induced neuropathic pain may be attributed to their anti-oxidant, anti-inflammatory properties and reduced calcium deposition in sciatic nerve., Competing Interests: Declaration of competing interest We declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Clinical evidence suggests that Esketamine (ESK) is an effective treatment for depression. However, the effects of Esketamine in treating depression-like behavior induced by neuropathic pain is unclear. The underlying molecular mechanisms require further investigation to provide new therapeutic targets for the treatment of clinical neuropathic pain-related depression., Methods: A neuropathic pain-related depression model was established in rats with spared nerve injury (SNI). Male Sprague-Dawley rats were randomly divided into four groups: Sham Group, SNI group, SNI + Normal Saline (NS) Group and SNI + ESK5mg/kg Group. Mechanical pain thresholds were measured to assess pain sensitivity in SNI rats. On the 14th day after surgery a forced swim test and sucrose preference test were used to evaluate the depressive-like behavior of rats in each group. Further, a proteomic analysis was used to quantify differentially expressed proteins. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to explore the main protein targets of SNI in the medial prefrontal cortex. The expression of proteins was detected by Western blotting., Results: A neuropathic pain-related depression model was established. Compared with the Sham group, the mechanical pain threshold was decreased significantly (13.2 ± 1.0 vs. 0.7 ± 0.01 g n = 8), while immobility on the forced swim test was also decreased (93.1 ± 7.4 vs. 169.5 ± 9.6 s n = 8), and sucrose preference rate was significantly increased (98.8 ± 0.3 vs. 73.1 ± 1.4n = 7) in SNI group rats. Compared with the SNI + NS group, the mechanical pain threshold was not statistically significant, while immobility on the forced swim test was clearly decreased (161.1 ± 11.6 vs. 77.9 ± 5.0 s n = 8), and sucrose preference rate was significantly increased (53.1 ± 8.9 vs. 96.1 ± 1.4n = 7) in SNI + ESK5mg/kg group rats. To further investigate the underlying mechanism, we employed proteomics to identify proteins exhibiting more than a 1.2-fold difference (P < 0.05) in expression levels within each group for subsequent analysis. Relative to the Sham group, 88 downregulated and 104 up-regulated proteins were identified in the SNI group, while 120 and 84 proteins were up- and down-regulated in the Esketamine treatment group compared with the SNI + NS group. Compared with Sham group, the expressions of mGluR5 and Homer1a were up-regulated in the medial prefrontal cortex (mPFC) in SNI group (mGluR5:0.97 ± 0.05 vs 1.47 ± 0.15, Homer1a:1.03 ± 0.06 vs 1.46 ± 0.16n = 6), and down-regulated after intervention with Esketamine (mGluR5:1.54 ± 0.11 vs 1.06 ± 0.07, Homer1a:1.51 ± 0.13 vs 1.12 ± 0.34n = 6)., Conclusions: Low-dose Esketamine appeared to relieve depression-like behavior induced by neuropathic pain. The Homer1a-mGluR5 signaling pathway might be the mechanism of antidepressant effect of Esketamine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

α-conotoxins (α-Ctxs), a class of disulfide-rich conopetides, are excellent drug leads due to their small size, high selectivity, and potency for specific membrane receptors and ion channels involved in pain transmission. However, their high susceptibility to proteolytic degradation limits their therapeutic potential. In this study, we designed and synthesized a series of conformationally stable analogues of α-Ctx Mr1.1[S4Dap] using various structural optimization strategies. The Mr1.1[S4Dap, C16Pen] analogue maintained potency at human α9α10 nicotinic acetylcholine receptors, with a half-maximal inhibitory concentration (IC 50 ) of 4 nM. It exhibited over a 5-fold increase in serum stability compared to Mr1.1[S4Dap], without disrupting its overall conformation. Furthermore, intravenous application of Mr1.1[S4Dap, C16Pen] showed potent analgesic activity in oxaliplatin-induced cold allodynia, indicating a high potential for drug development. Overall, the results from this study provide valuable insights for optimizing the serum stability of disulfide-rich peptides in future therapeutic applications.

Neuropathic pain (NP) is a widespread public health problem that existing therapeutic treatments cannot manage adequately; therefore, novel treatment strategies are urgently required. G-protein-coupled receptors are important for intracellular signal transduction, and widely participate in physiological and pathological processes, including pain perception. Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are predominantly implicated in central sensitization, which can lead to hyperalgesia and allodynia. Many orthosteric site antagonists targeting Group I mGluRs have been found to alleviate NP, but their poor efficacy, low selectivity, and numerous side effects limit their development in NP treatment. Here we reviewed the advantages of Group I mGluRs negative allosteric modulators (NAMs) over orthosteric site antagonists based on allosteric modulation mechanism, and the challenges and opportunities of Group I mGluRs NAMs in NP treatment. This article aims to elucidate the advantages and future development potential of Group I mGluRs NAMs in the treatment of NP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Vincristine (VCR), an anti-tubulin chemotherapy agent, is known to cause peripheral and central nerve damage, inducing severe chemotherapy-induced peripheral neuropathy (CIPN). Although melatonin has been recently recognized for its potential anti-neuropathic effects, its efficacy in countering VCR-induced neuropathy remains unclear. This study examines the neuroprotective potential of melatonin against VCR-induced neuropathy using a rat model. Neuropathic pain was induced through 10 VCR injections (0.1 mg/kg/day i.p.), administered in two five-day cycles with a two-day break. Melatonin treatment started two days before VCR administration and continued daily throughout the experiment. Rats were assigned to five groups: control, VCR, and three melatonin-treated groups receiving VCR with melatonin (5, 10, or 20 mg/kg/day i.p.). We assessed mechanical (von-Frey and Randall-Selitto tests) and thermal (hot-plate and tail-flick tests) hyperalgesia, motor coordination (rotarod test), and sciatic nerve conduction velocity (NCV). Changes in body weight, spinal cord histopathology (H&E), and proinflammatory markers (TNF-α, IL-1β, and IL-6), reactive astrocytes (GFAP) and microglial cells (IBA-1) were also assessed, as well as spinal cord degeneration (Nissl stain) and demyelination (LFB stain and MBP). Finally, the effect of melatonin on the cytotoxic activity of VCR against EL4 lymphoma cells was assessed using an MTT assay. Our results indicated that melatonin coadministration with VCR preserved spinal cord architecture, elevated nociceptive thresholds, improved motor coordination, enhanced NCV, and maintained normal body weight gain. Melatonin also reduced inflammation, decreased reactive astrocytes and microglia, and prevented neurodegeneration and demyelination in the spinal cord. Importantly, melatonin did not affect VCR's cytotoxic activity in cancer cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Engie S. El-Sawaf reports financial support was provided by Future University in Egypt (FUE). Engie S. El-Sawaf reports financial support was provided by United States Agency for International Development (USAID). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Given the unclear, complex pathogenesis of neuropathic pain and the potential of paeoniflorin in relieving neuropathic pain, this study aimed to further clarify the therapeutic effect of paeoniflorin on neuropathic pain and to preliminarily explore the possible protective mechanisms of paeoniflorin. Chronic constrictive injury-induced Sprague Dawley rats and lipopolysaccharide-induced BV-2 cells were used for in vivo and in vitro experiments, respectively. The exosome uptake assay of mouse astrocytes (PKH-67 fluorescent labeling) and the mechanical nociceptive assay (the von Frey fibrous filaments) were performed. The effects of paeoniflorin and its downstream mechanisms on microglial and astrocyte activation, inflammation-associated proteins and exosome marker were determined. Paeoniflorin alleviated mechanical abnormal pain, decreased levels of ionized calcium binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein, Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1, inflammatory factor) and High Mobility Group Box 1 (HMGB1, inflammation-related protein), and inhibited neuronal apoptosis in chronic constrictive injury rats or lipopolysaccharide-induced BV-2 cells. However, these effects were offset by HSP90AA1 overexpression in lipopolysaccharide-induced BV-2 cells. Exosomes of BV-2 cells could be absorbed by mouse astrocytes. In addition, HSP90AA1 overexpression reversed the effects of paeoniflorin on HMGB1 expression and inflammatory factors and proteins in mouse astrocytes co-cultured with exosome. Collectively, paeoniflorin alleviates neuropathic pain and inhibits inflammatory responses in chronic constrictive injury by modulating microglia-astrocyte crosstalk through HSP90AA1/HMGB1 pathways, which further evidences the potential of paeoniflorin in the treatment of neuropathic pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone., (© 2024 John Wiley & Sons Australia, Ltd.)

This study aimed to explore the potential antiallodynic effects of rosmarinic acid, a natural antioxidant with a demonstrated safety profile across a broad dose range. Using a chronic constriction injury-induced neuropathic pain model, the impact of rosmarinic acid on allodynia was investigated. Furthermore, the involvement of adrenergic and opioidergic mechanisms in its activity was assessed. To evaluate rosmarinic acid's efficacy, doses of 10, 20, and 40 mg/kg were administered and the electronic von Frey test was utilized along with an activity cage apparatus. % MPE values were calculated to gauge the extent of pain relief. Mechanistic insights were obtained by pretreating animals with the β-adrenergic receptor antagonist propranolol, the α1-adrenergic receptor antagonist prazosin, α2-adrenergic receptor antagonist yohimbine, and the opioid receptor antagonist naloxone. Rosmarinic acid demonstrated a statistically significant antiallodynic effect that was independent of locomotor activity. This effect was noteworthy as it resembled both the level and duration of relief provided by pregabalin. Additionally, the %MPE value of the group treated with 40 mg/kg rosmarinic acid showed a significant difference compared to the value of the pregabalin-treated group (P<0.001). Pre-administration of the antagonists revealed that the antiallodynic activity was shown to be mediated by the stimulation of opioid and adrenergic receptors, with a primary contribution from α2-adrenergic receptor stimulation. Our findings suggest that rosmarinic acid may hold promise as a potential therapeutic agent for neuropathic pain. By elucidating the involvement of adrenergic and opioidergic mechanisms, we have provided valuable preclinical data that could inform novel treatment approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Decursin, a major active ingredient from Angelica gigas Nakai, has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of decursin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with decursin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although decursin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons, and restored nerve conduction velocity and blood flow in sciatic nerves. Notably, the analgesic actions of decursin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of decursin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Gabapentinoids increasingly utilized for neuropathic pain, possibly to curb opioid prescribing. At the same time, data suggest subsequent increases in misuse and overdose of gabapentinoids, often in mixed overdoses. We sought to determine national trends and characteristics of gabapentinoid prescribing, including co-use with opioids, from the emergency department (ED)., Methods: This is a retrospective review of the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2012 to 2021. Our primary outcome was the trend in ED visits in which gabapentinoids were prescribed at discharge. Secondarily, we identified trends in gabapentinoid and opioid co-prescribing and gabapentin and pregabalin prescribing at ED discharge. We examined demographic data and used descriptive statistics, Shapiro Wilke's test, Pearson's Spearman's rho (SR) or Pearson's correlation coefficient (PC) as applicable. Neural networks were used to identify the most important predictors of opioid utilization during the same visit., Results: Between 2012 and 2021, there were an estimated 7,242,694 (0.53% of all ED visits) visits in which gabapentinoids were prescribed at ED discharge. Prescriptions increased from a total of 138,479 (0.1%) in 2012 to 893,495 (0.63%) in 2021 (PC: 0.85, p < 0.001). Opioids were co-prescribed in 27.2% of all visits in which gabapentinoids were prescribed, with no change over time (PC: -0.47, p = 0.09). Pregabalin prescription increased linearly over time (PC: 0.64, p = 0.02). The most important predictors of opioid administration or co-prescribing were whether an alternative provider (e.g., consult or nurse practitioner) saw the patient (100%), insurance (94.4%), age (75.9%), and region (75.2%)., Conclusion: Despite an association of misuse and overdose, often associated with opioids, gabapentinoids were increasingly prescribed at ED discharge. While these agents may be safer alternatives to opioids, misuse may be an associated consequence of increased prescribing, which warrants further investigation., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The current analgesics often prevent patients from getting effective treatment due to their adverse effects. Cannabidiol (CBD) is well tolerated, has few side effects and has been extensively investigated in analgesia. However, its oral bioavailability is extremely low. In order to solve this problem, we developed the cannabidiol nanocrystals (CBD-NC) in the earlier stage., Methods: In this study, we evaluated the nociceptive behaviours associated with neuropathic pain (NP) induced by the spared nerve injury (SNI) model. Assessment of pain threshold was evaluated by paw withdraw threshold (PWT) and paw withdrawal latency (PWL). The improving effect on the motor dysfunction was determined by rota-rod testing. To assess the neuroprotective effect, nerve demyelination and expression of peripheral myelin protein PMP22 were measured with myelin sheath staining and western blotting. Protein expressions in microglia of spinal cord were tested by western blot to explore the underlying mechanism., Results: Compared with the CBD oil solution, CBD-NC significantly reduced mechanical allodynia and thermal hyperalgesia in rats. CBD-NC could improve motor dysfunction induced by SNI in rats, significantly reverse the demyelination and increase the expression of the marker protein of peripheral myelin. Underlying spinal analgesic mechanism of microglia and related factors were preliminarily confirmed., Conclusions: CBD-NC administration is an effective treatment for NP associated with SNI, and the analgesic effect of CBD-NC was significantly better than that of CBD oil sol. By contrast, CBD-NC has a fast-acting and long-term effect in the treatment of NP. Our study further supports the potential therapeutic effect of CBD-NC on NP., Significance: The absolute bioavailability of the CBD-NC intramuscular injection formulation can reach 203.31%, which can solve the problem of low oral bioavailability. This research evaluated the therapeutic effect of CBD-NC on NP associated with the SNI model for the first time. All available date showed that whatever the analgesic or neuroprotective effect of CBD-NC, it was significantly better than that of CBD oil sol., which was consistent with the results of the pharmacokinetic. This research supports the initiation of more trials testing the efficacy of CBD-NC for treating NP., (© 2024 European Pain Federation ‐ EFIC®.)

Abstract: Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors ( Cnr1 and Oprm1 ) is coexpressed across different neuron clusters. Myc-CB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain., (Copyright © 2024 International Association for the Study of Pain.)

Abstract: Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain. We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity., (Copyright © 2024 International Association for the Study of Pain.)

Purpose: The primary aim of this study was to compare time to odontogenic keratocyst (OKC) recurrence with 5-fluorouracil (5-FU) versus modified Carnoy's solution (MCS) following enucleation and curettage and peripheral ostectomy. The secondary aim was to compare the frequency (%) of permanent peripheral nerve injury characterized by hypoesthesia and neuropathic pain present at 12 months or more after surgery with 5-FU versus MCS., Methods: The Cox hazard ratio was calculated to compare time to recurrence between the 2 groups. To compare the frequencies of permanent nerve damage, we fitted a fixed-effects model to the data and calculated the risk ratio. Other variables collected were sex, age, follow-up time, and cyst size., Results: No significant differences in sex, age, follow-up time, and cyst size were found. The median follow-up time for all patients was 60 months (range: 12-180 months, Q 1  = 32 months, Q 3  = 86 months, interquartile range = 54 months). Of the 114 patients treated with MCS, 27 recurrences with a median recurrence time of 42 months (range = 12-108 months, Q 1  = 26.3 months, Q 3  = 54 months, interquartile range = 27.7 months) were recorded; no recurrences were observed among the 99 patients treated with 5-FU (hazard ratio = 0.02, 95% CI = 0.00018-0.16, P = 2.27e-07). Of the 112 patients treated with MCS, there were 20 (17.86%) instances of permanent peripheral nerve injury; of the 98 patients treated with 5-FU, there were 7 (7.14%) instances of permanent peripheral nerve injury (risk ratio = 0.44, 95% CI = 0.20-0.97, P = .04)., Conclusion: The results of this meta-analysis significantly favored 5-FU over MCS for lower OKC recurrence and peripheral nerve injury, supporting the use of 5-FU as the superior adjuvant following enucleation and curettage and peripheral ostectomy for the treatment of OKCs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic pain is a constantly recurring and persistent illness, presenting a formidable healthcare challenge for patients and physicians alike. Current first-line analgesics offer only low-modest efficacy when averaged across populations, further contributing to this debilitating disease burden. Moreover, many recent trials for novel analgesics have not met primary efficacy endpoints, which is particularly striking considering the pharmacological advances have provided a range of highly relevant new drug targets. Heterogeneity within chronic pain cohorts is increasingly understood to play a critical role in these failures of treatment and drug discovery, with some patients deriving substantial benefits from a given intervention while it has little-to-no effect on others. As such, current treatment failures may not result from a true lack of efficacy, but rather a failure to target individuals whose pain is driven by mechanisms which it therapeutically modulates. This necessitates a move towards phenotypical stratification of patients to delineate responders and non-responders in a mechanistically driven manner. In this article, we outline a bench-to-bedside roadmap for this transition to mechanistically informed personalised pain medicine. We emphasise how the successful identification of novel analgesics is dependent on rigorous experimental design as well as the validity of models and translatability of outcome measures between the animal model and patients. Subsequently, we discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics. Finally, we show how stratification approaches can be brought into clinical routine to the benefit of patients., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute stress normally engages descending brain pathways to produce an antinociceptive response, known as stress-induced analgesia. Paradoxically, these descending pain modulatory pathways are also involved in the maintenance of the abnormal pain associated with chronic neuropathic pain. It remains unclear how stress-induced analgesia is affected by neuropathic pain states. We therefore examined the impact of a chronic constriction nerve-injury (CCI) model of neuropathic pain on restraint stress-induced analgesia in C57BL/6 mice. Thirty minutes of restraint stress produced analgesia in the hotplate thermal nociceptive assay that was less in CCI compared to control mice who underwent a sham-surgery. In sham but not CCI mice, stress-induced analgesia was reduced by the opioid receptor antagonist naltrexone. The cannabinoid CB 1 receptor antagonist AM281 did not affect stress-induced analgesia in either sham or CCI mice. Low-dose pre-treatment with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195 increased stress-induced analgesia in CCI but not sham mice. The JZL195 enhancement of stress-induced analgesia in CCI mice was abolished by AM281 but was unaffected by naltrexone. These findings indicate that the acute opioid-mediated analgesic response to a psychological stressor is disrupted in a nerve-injury model of neuropathic pain. Importantly, this impairment of stress-induced analgesia was rescued by blockade of endocannabinoid breakdown via a cannabinoid CB 1 receptor dependent mechanism. These findings suggest that subthreshold treatment with endocannabinoid degradation blockers could be used to alleviate the disruption of endogenous pain control systems in a neuropathic pain state., (© 2024 International Society for Neurochemistry.)

Background: Gabapentin, a widely prescribed medication for various neuropathic pain conditions, has demonstrated efficacy in managing diverse neurological disorders. While conventional side effects are well-documented, a growing body of evidence suggests the existence of atypical side effects, necessitating comprehensive exploration. This paper aims to systematically review and summarize the literature on the atypical side effects of gabapentin, shedding light on manifestations beyond the conventional spectrum., Methods: A systematic review was conducted, encompassing peer-reviewed articles published up to the knowledge cutoff date in November 2023. Databases, specifically PubMed, were searched for relevant studies, focusing on atypical side effects such as myoclonus, ataxia, pediatric aggression, respiratory depression, pneumonia, pregnancy complications, sleep interference, encephalopathy, peripheral edema, suicidal ideation, dyskinesia, anorgasmia, and myopathy. Inclusion criteria comprised studies with a focus on gabapentin-related atypical side effects, published in recognized journals and involving human subjects., Results: The review identified a spectrum of atypical side effects associated with gabapentin use, ranging from neurological manifestations like myoclonus and ataxia to behavioral changes such as pediatric aggression and suicidal ideation. Additionally, respiratory complications, pregnancy-related issues, sleep disturbances, and rare complications like encephalopathy and myopathy were observed. Literature synthesis provided insights into the incidence, clinical presentation, and potential mechanisms underlying these atypical side effects., Conclusion: This comprehensive review highlights the diverse range of atypical side effects associated with gabapentin use, expanding beyond conventional knowledge. Healthcare practitioners must be cognizant of these manifestations, recognizing their potential impact on patient well-being. As clinical decision-making relies on a thorough understanding of a medication's side effect profile, this review contributes to enhancing awareness and fostering informed practices in the prescription and management of gabapentin. Further research is warranted to elucidate the mechanisms and risk factors associated with these atypical side effects, refining our understanding of gabapentin's safety profile., (© 2024 World Institute of Pain.)

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta-9-tetrahydrocannabinol (THC). While there have been some positive findings, meta-analyses of this clinical work indicates that this effectiveness is limited and hampered by side-effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC-containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side-effects of cannabis., (© 2023 International Society for Neurochemistry.)

Chemotherapy-induced peripheral neuropathy (CIPN) affects a significant majority of cancer patients, with up to 80% experiencing this severe and dose-limiting side effect while undergoing anti-cancer treatment. CIPN can be induced by a variety of drugs commonly employed in the management of both solid tumors and hematologic cancers. The inadequacies in comprehending the pharmacological interventions associated with CIPN and the subsequent signaling pathways have significantly contributed to the disappointing outcomes of several drugs in clinical trials. Recent investigations in pain research have demonstrated a growing inclination toward addressing neuro-inflammation as a strategy for managing chronic pain conditions. Notably, toll-like receptor-4 (TLR-4) has emerged as a key player in immune system activation and is undergoing extensive research. In this review, we emphasize the potential role of TLR-4 in neuropathic pain, highlighting its promise as a target for CIPN treatment. Furthermore, we explore and analyse the intricate interplay between TLR-4, diverse immune cells, downstream pathways, and receptors within the context of CIPN. A comprehensive exploration of these interactions provides valuable insights into the central role of TLR-4 in CIPN development, paving the way for potential ground-breaking therapeutic approaches to alleviate this debilitating condition., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Ethnopharmacological Relevance: Jinmaitong (JMT) is a prescription of Traditional Chinese Medicine that is composed of 12 crude drugs. It has been used in the treatment of diabetic neuropathic pain (DNP) for more than 30 years., Aim of Study: Microglia are thought to play an important role in neuropathic pain. This study aimed to evaluate the protective effect of JMT against DNP and to investigate the underlying mechanisms in which the microglia and JAK2/STAT3 signaling pathway were mainly involved., Materials and Methods: The chemical composition of JMT was analyzed using liquid chromatography tandem mass spectrometry. The diabetes model was constructed using 11 to 12-week-old male Zucker diabetic fatty (ZDF) rat (fa/fa). The model rats were divided into 5 groups and were given JMT at three dosages (11.6, 23.2, and 46.4 g/kg, respectively, calculated as the crude drug materials), JAK inhibitor AG490 (positive drug, 10 μg/day), and placebo (deionized water), respectively, for eight weeks (n = 6). Meanwhile, Zucker lean controls (fa/+) were given a placebo (n = 6). Body weight was tested weekly and blood glucose was monitored every 2 weeks. The mechanical allodynia and heat hyperalgesia were assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. After treatment, the microglia activation marker Iba-1, CD11B, CD68, neuroinflammatory mediators, and mediators of the JAK2/STAT3 signaling pathway were compared between different groups. The mRNA and protein levels of target genes were assessed by quantitative real-time PCR and Western Blot, respectively., Results: We found that JMT significantly inhibited the overactivation of microglia in spinal cords, and suppressed neuroinflammation of DNP model rats, thereby ameliorating neurological dysfunction and injuries. Furthermore, these effects of JMT could be attributed to the inhibition of the JAK2/STAT3 signaling pathway., Conclusions: Our findings suggested that JMT effectively ameliorated DNP by modulating microglia activation via inhibition of the JAK2/STAT3 signaling pathway. The present study provided a basis for further research on the therapeutic strategies of DNP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABA B ) receptor-coupled Ca V 2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABA B receptor-coupled Ca V 2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatin-induced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

Background: Neuroinflammation and mitochondrial dysfunction have been implicated in the progression of neuropathic pain (NP) but can be mitigated by supplementation with gingerol-enriched ginger (GEG). However, the exact benefits of GEG for each sex in treating neuroinflammation and mitochondrial homeostasis in different brain regions and the colon remain to be determined., Objective: Evaluate the effects of GEG on emotional/affective pain and spontaneous pain behaviors, neuroinflammation, as well as mitochondria homeostasis in the amygdala, frontal cortex, hippocampus, and colon of male and female rats in the spinal nerve ligation (SNL) NP model., Methods: One hundred rats (fifty males and fifty females) were randomly assigned to five groups: sham + vehicle, SNL + vehicle, and SNL with three different GEG doses (200, 400, and 600 mg/kg BW) for 5 weeks. A rat grimace scale and vocalizations were used to assess spontaneous and emotional/affective pain behaviors, respectively. mRNA gene and protein expression levels for tight junction protein, neuroinflammation, mitochondria homeostasis, and oxidative stress were measured in the amygdala, frontal cortex, hippocampus, and colon using qRT-PCR and Western blot (colon)., Results: GEG supplementation mitigated spontaneous pain in both male and female rats with NP while decreasing emotional/affective responses only in male NP rats. GEG supplementation increased intestinal integrity (claudin 3) and suppressed neuroinflammation [glial activation (GFAP, CD11b, IBA1) and inflammation (TNFα, NFκB, IL1β)] in the selected brain regions and colon of male and female NP rats. GEG supplementation improved mitochondrial homeostasis [increased biogenesis (TFAM, PGC1α), increased fission (FIS, DRP1), decreased fusion (MFN2, MFN1) and mitophagy (PINK1), and increased Complex III] in the selected brain regions and colon in both sexes. Some GEG dose-response effects in gene expression were observed in NP rats of both sexes., Conclusions: GEG supplementation decreased emotional/affective pain behaviors of males and females via improving gut integrity, suppressing neuroinflammation, and improving mitochondrial homeostasis in the amygdala, frontal cortex, hippocampus, and colon in both male and female SNL rats in an NP model, implicating the gut-brain axis in NP. Sex differences observed in the vocalizations assay may suggest different mechanisms of evoked NP responses in females.

Back Ground: 7-Methoxycoumarin (7-MC) is well recognized for its anti-inflammatory and anti-nociceptive actions. Its capacity to lessen neuropathic pain hasn't been documented yet. Hence the impact of 7-MC on vincristine-induced peripheral neuropathic pain in rodents was investigated. The investigation also looked at the impact of 7-MC in reducing neuropathic pain via voltage-gated calcium channels and phospholipase enzyme inhibition using pertinent in vitro and in silico methods., Methods and Results: Vincristine (0.1 mg/kg, i.p., daily) was administered continuously for 7 days to induce peripheral neuropathic pain in mice, with cold allodynia and thermal hyperalgesia and evaluated on the 8th day using the acetone bubble test and hot water tail immersion test. In order to derive the mechanistic approach for ameliorating neuropathic pain, the role of 7-MC in the inhibition of the phospholipase enzyme, gene expression studies on voltage-gated calcium channels using mouse BV2 microglial cells and in silico studies for its calcium channel binding affinity were also performed. The test compounds reduced vincristine-induced cold allodynia and thermal hyperalgesia in mice in a dose-dependent experiments. In vitro studies on phospholipase inhibition by 7-MC showed an IC 50 of 27.08 µg/ml and down-regulated the gene expression of calcium channels in the BV2 microglial cell line. In silico docking scores for 7-MCwere higher than the standard drug gabapentin., Conclusion: The compound 7-MC has shown promise in alleviating vincristine-induced peripheral neuropathicin mice. Studies conducted in parallel, both in silico and in vitro have demonstrated that 7-MC effectively reduces neuropathic pain. This pain reduction is achieved through two mechanisms: inhibiting the phospholipase enzyme and blocking voltage-gated calcium channels., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis : cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. SIGNIFICANCE STATEMENT: Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study, we evaluated five minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that four of the five minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization., (Copyright © 2024 by The Author(s).)

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7-10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. The GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal-dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Neuropathic pain (NeP) is a complex and debilitating condition that impacts millions of people globally. Although various treatment options exist, their effectiveness is often limited, and they can be accompanied by significant side effects. In recent years, there has been increasing interest in targeting the N-methyl-D-aspartate receptor (NMDAR) as a potential therapeutic approach to alleviate different types of neuropathic pain. This narrative review aims to provide a comprehensive examination of NMDAR antagonists, specifically ketamine, memantine, methadone, amantadine, carbamazepine, valproic acid, phenytoin, dextromethorphan, riluzole, and levorphanol, in the management of NeP. By analyzing and summarizing current preclinical and clinical studies, this review seeks to evaluate the efficacy of these pharmacologic agents in providing adequate relief for NeP.

Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I 1 -receptor agonist LNP599 and whether the attenuation involves co-activation of α 2 -adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb. Additionally, GTPγS radioligand binding assay, β-arrestin recruitment and intracellular cAMP levels were used for receptor profiling in vitro. LNP599 (imidazoline I 1 receptor agonist) and clonidine (α 2 -adrenoceptor agonist) produced equal dose-related mechanical antihypersensitivity effects in both sexes. LNP599 attenuated heat nociception preferentially in males, while clonidine reduced heat nociception equally in males and females. Carbophenyline (another imidazoline I 1 receptor agonist) had no significant effect on mechanical hypersensitivity or heat nociception in males or females. Mechanical antihypersensitivity and heat antinociception induced by LNP599 in SNI males was prevented by pretreatments with yohimbine or atipamezole (two α 2 -adrenoceptor antagonists) but not by efaroxan (a mixed imidazoline I 1 receptor/α 2 -adrenoceptor antagonist). In vitro assays indicated that LNP599 does not activate α 2A - or other subtypes of α 2 -adrenoceptors. However, LNP599 was a weak partial agonist for 5-HT 2B receptors and bound to sigma-1 and sigma-2 receptors that all are involved in modulation of spinal nociception. The results indicate that the suppression of neuropathic pain hypersensitivity by LNP599 is not due to action on spinal imidazoline I 1 receptors, but rather due to indirect activation of spinal α 2 -adrenoceptors., Competing Interests: Declaration of Competing Interest Three of the authors (A.V., A.D., and A.K.) are employees of a pharmaceutical company (Orion Pharma). One of the authors (J.L.) has received funding from a pharmaceutical company (Orion Pharma). Other authors (H.W. and A.P.) declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain results from damage to nerves or the brain, and is characterized by symptoms such as allodynia, spontaneous pain, and hyperalgesia. The causes of this type of pain are intricate, which can make it difficult to treat. Sodium aescinate (SA), a natural extract from horse chestnut tree seeds, has been shown to act as a neuroprotector by inhibiting microglia activation. This study aims to explore the therapeutic potential of SA for neuropathic pain and the molecular mechanisms regulated by SA treatment. Through in vivo animal models and experiments, we found that SA treatment significantly reduced mechanical allodynia and heat hyperalgesia in neuropathic pain models. Additionally, SA inhibited O-GlcNAc-transferase (OGT)-induced O-GlcNAcylation (O-GlcNAc) modification in neuropathic pain mice. OGT overexpression could impede the therapeutic effects of SA on neuropathic pain. Further investigation revealed that Toll-like receptor 3 (TLR3), stabilized by OGT-induced O-GlcNAc modification, could activate the Mitogen activated protein kinase (MAPK) signaling pathway. Further in vivo experiments demonstrated that TLR3-mediated p38 mitogen-activated protein kinase (p38MAPK) activation is involved in SA-mediated relief of neuropathic pain. In conclusion, this study uncovers a novel molecular pathway deactivated by SA treatment in neuropathic pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain (NP) is associated with astrocytes activation induced by nerve injury. Reactive astrocytes, strongly induced by central nervous system damage, can be classified into A1 and A2 types. Vitexin, a renowned flavonoid compound, is known for its anti-inflammatory and analgesic properties. However, its role in NP remains unexplored. This study aims to investigate the effects of vitexin on astrocyte polarization and its underlying mechanisms. A mouse model of NP was established, and primary astrocytes were stimulated with sphingosine-1-phosphate (S1P) to construct a cellular model. The results demonstrated significant activation of spinal astrocytes on days 14 and 21. Concurrently, reactive astrocytes predominantly differentiated into the A1 type. Western blot analysis revealed an increase in A1 astrocyte-associated protein (C3) and a decrease in A2 astrocyte-associated protein (S100A10). Serum S1P levels increased on days 14 and 21, alongside a significant upregulation of Sphingosine-1-phosphate receptor 1 (S1PR1) mRNA expression and elevated expression of chemokines. In vitro, stimulation with S1P inhibited the Phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) signaling pathway and autophagy flux, promoting polarization of astrocytes towards the A1 phenotype while suppressing the polarization of A2 astrocytes. Our findings suggest that vitexin, acting on astrocytes but not microglia, attenuates S1P-induced downregulation of PI3K/Akt signaling, restores autophagy flux in astrocytes, regulates A1/A2 astrocyte ratio, and reduces chemokine and S1P secretion, thereby alleviating neuropathic pain caused by nerve injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Neuropathic pain, a common symptom of several disorders, exerts a substantial socioeconomic burden worldwide. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel predominantly ex-pressed in nociceptive neurons, plays a pivotal role in nociception, by detecting various endogenous and exogenous stimuli, including heat, pro-inflammatory mediators, and physical stressors. Dysregulation of TRPV1 signaling further contributes to the pathophysiology of neuropathic pain. Therefore, targeting TRPV1 is a promising strategy for developing novel analgesics with improved efficacy and safety profiles. Several pharmacological approaches to modulate TRPV1 activity, including agonists, antagonists, and biological TRPV1 RNA interference (RNAi, small interfering RNA [siRNA]) have been explored. Despite preclinical success, the clinical translation of TRPV1-targeted therapies has encountered challenges, including hyperthermia, hypothermia, pungency, and desensitization. Nevertheless, ongoing research efforts aim to refine TRPV1-targeted interventions through structural modifications, development of selective modulators, and discovery of natural, peptide-based drug candidates. Herein, we provide guidance for researchers and clinicians involved in the development of new interventions specifically targeting TRPV1 by reviewing the existing literature and highlighting current research activities. This study further discusses potential future research endeavors for enhancing the efficacy, safety, and tolerability of TRPV1 candidates, and thereby facilitates the translation of these discoveries into effective clinical interventions to alleviate neuropathic pain disorders., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain generally affects 7-10% population worldwide and an estimated ∼1 in every 20 individuals in western countries suffer and burden to society. The most limiting factor with existing therapies includes dose escalation issues, off-target side effects and poor translation of randomized trials into clinical practice. Neuropathic pain is a broad term that comprises direct injury/damage to the central and/or peripheral nervous system, leads to maladaptive changes in neuronal as well as in non-neuronal cells, which further contributes to the spontaneous pain, sensory and motor deficit along with altered sensitivity towards the noxious as well as non-noxious stimulus. Transient receptor potential (TRP) channels are polymodal, non-specific cation channels that operate as biosensors to various mechanical and chemical stimuli, including hyperosmolarity, shear stress, heat, mechanical stretch, extracellular ATP, and other products of inflammation. Modulation of these channels leads to various physiological and pathophysiological manifestations at molecular and cellular levels, leading to diseases including neuropathic pain. There are several molecules targeting TRP channels for neuropathic pain in pre-clinical studies, clinical trials and in the market. This review highlights the critical involvement of various pharmacological modulators for TRP channels targeting neuropathic pain and their possible outcomes to harness the therapeutic potential of TRP channels., Competing Interests: Declaration of competing interest The authors have no financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Opioid and cannabinoid therapies for chronic pain conditions including neuropathic pain are controversial. Understanding patient and prescribing factors contributing to risks and implementing risk mitigation strategies optimizes outcomes., Latest Developments: The ongoing transformation from a biomedical model of pain care toward a biopsychosocial model has been accompanied by a shift away from opioid therapy for pain, in particular for chronic pain. Opioid overdose deaths and opioid use disorder have greatly increased in the last several decades, initially because of increases in opioid prescribing and more recently associated with illicit drug use, in particular fentanyl derivatives. Opioid risk mitigation strategies may reduce risks related to opioid prescribing and tapering or discontinuation. Opioid therapy guidelines from the Centers for Disease Control and Prevention have become the consensus best practice for opioid therapy. Regulatory agencies and licensing medical boards have implemented restrictions and other mandates regarding opioid therapy. Meanwhile, interest in and use of cannabinoids for chronic pain has grown in the United States., Essential Points: Opioid therapy is generally not recommended for the chronic treatment of neuropathic pain conditions. Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions (such as postherpetic neuralgia), and only as part of a multimodal treatment regimen. Opioid risk mitigation strategies include careful patient selection and evaluation, patient education and informed consent, querying the state prescription drug monitoring programs, urine drug testing, and issuance of naloxone as potential rescue medication. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required. There is evidence for the efficacy of cannabinoids for neuropathic pain, with meaningful response rates in select patient populations., (Copyright © 2024 American Academy of Neurology.)

Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression., Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior., Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice., Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Introduction: This study explores the interaction between cytokines, cell-mediated immunity (T cells, B cells, and NK cells), and prolonged morphine administration in chronic neuropathic pain patients without cancer-related issues. Despite evidence of opioid immunomodulation, few studies have compared these interactions., Methods: In a cross-sectional and comparative study, 50 patients with chronic low back radicular pain ("Failed Back Surgery Syndrome") were categorized into intrathecal morphine infusion (IT group, n = 18), oral morphine (PO group, n = 17), and non-opioid treatment (NO group, n = 15). Various parameters, including plasma and cerebrospinal fluid (CSF) cytokine concentrations, lymphocyte immunophenotyping, opioid escalation indices, cumulative morphine dose, and treatment duration, were assessed., Results: CSF IL-8 and IL-1β concentrations exceeded plasma levels in all patients. No differences in T, B, and NK lymphocyte numbers were observed between morphine-treated and non-treated patients. Higher plasma IL-5 and GM-CSF concentrations were noted in IT and PO groups compared to NO. CSF IFNγ concentrations were higher in PO and NO than IT. Positive correlations included CD4 concentrations with opioid escalation indices, and negative correlations involved NK cell concentrations, CSF TNFα concentrations, and opioid escalation indices. Positive correlations were identified between certain cytokines and pain intensity in IT patients, and between NK cells and cumulative morphine dose. Negative correlations were observed between CSF IL-5 concentrations and pain intensity in IT and PO, and between opioid escalation indices and CSF cytokine concentrations in PO and IT., Conclusion: Associations between cytokines, cellular immunity, and prolonged morphine treatment, administered orally and intrathecally were identified., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cold atmospheric plasma (CAP) has been employed as a therapy against both acute and chronic skin lesions, contaminated or not, and has effects on angiogenesis and reepithelialization promoting healing. In this context, the present study aimed to evaluate the effects of a CAP jet associated with pharmacological treatment described by the 2015 AAHA/AAFP pain management guidelines and the 2022 WSAVA guidelines for the recognition, assessment, and treatment of pain, on the healing of chronic skin lesions caused by a pruritic reaction resulting from post-surgical neuropathic pain. To this end, a single CAP application was performed on a feline patient with a 6 months old recurrent contaminated cervical skin lesions along with administration of ketamine (10 µg/kg/min) following the prescription of prednisone (1 mg/kg, SID, 6 days), gabapentin (8 mg/kg, BID, 60 days) and amitriptyline (0.5 mg /kg, SID, 60 days). A single application of plasma associated with an NMDA antagonist, anti-inflammatory steroid, tricyclic antidepressant and gabapentinoid thus provided a significant improvement in the macroscopic appearance of the lesion within 10 days, and the owner reported the cessation of intense itching within the first four hours after treatment and a consequent improvement in the animal's quality of life. The medical treatment was finished almost a year since the writing of this paper, without clinical or reported recurrent signs of the condition. Therefore, we observed that single dose CAP application associated with ketamine, gabapentin, amitriptyline and prednisone leads to significant healing of chronically infected skin lesions resulting from post-surgical neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect., Methods: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG)., Results: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1β and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG., Conclusions: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

This study investigated Cerium oxide nanoparticles (CeONPs) effect on central neuropathic pain (CNP). The compressive method of spinal cord injury (SCI) model was used for pain induction. Three groups were formed by a random allocation of 24 rats. In the treatment group, CeONPs were injected above and below the lesion site immediately after inducing SCI. pain symptoms were evaluated using acetone, Radian Heat, and Von Frey tests weekly for six weeks. Finally, we counted fibroblasts using H&E staining. We evaluated the expression of Cx43, GAD65 and HDAC2 proteins using the western blot method. The analysis of results was done by PRISM software. At the end of the study, we found that CeONPs reduced pain symptoms to levels similar to those observed in normal animals. CeONPs also increased the expression of GAD65 and Cx43 proteins but did not affect HDAC2 inhibition. CeONPs probably have a pain-relieving effect on chronic pain by potentially preserving GAD65 and Cx43 protein expression and hindering fibroblast infiltration., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

µ-Opioid receptor agonists, the gold standard for analgesia, come with significant side effects when used chronically. Tolerance, defined as the decrease in analgesic activity after repeated use, remains a vital therapeutic obstacle as it increases the likelihood of dose escalation and potentially lethal side effects like respiratory depression. Previous experiments have shown that the endomorphin-1 analog, ZH853, is a specific µ-opioid receptor agonist with reduced side effects like tolerance and glial activation following chronic central administration in pain-naive animals. Here, we investigated the effects of chronic, peripheral administration of µ-opioid receptor agonists following neuropathic injury. Though µ-opioids are effective at reducing neuropathic pain, they are not recommended for first-line treatment due to negative side effects. Compared with chronic morphine, chronic ZH853 treatment led to decreased tolerance and reduced glial activation. Following twice-daily intravenous injections, morphine was less potent and had a shorter duration of antinociception compared with ZH853. Chronic morphine, but not chronic ZH853, elevated markers of activation/inflammation of astrocytes (glial fibrillary acidic protein), microglia (ionized calcium-binding adapter molecule 1), the proinflammatory cytokine tumor necrosis factor-α, and phosphorylated mitogen-activated protein (MAP) kinase p38 (pp38). By contrast, chronic ZH853 reduced ionized calcium-binding adapter molecule 1 and tumor necrosis factor-α relative to both morphine and vehicle, suggesting anti-inflammatory properties with respect to these markers. Glial fibrillary acidic protein and pp38 were not significantly different from vehicle but were significantly lower than morphine. This study demonstrates the effectiveness of chronic ZH853 for providing analgesia in a neuropathic pain state with reduced tolerance compared with morphine, potentially due to reductions in spinal glial activation. PERSPECTIVE: Neuropathic pain is generally undertreated and resistant to medication, and side-effects limit opioid treatment. Here, we show that, compared with an equiantinociceptive dose of morphine, chronic intravenous administration of endomorphin analog ZH853 led to prolonged antiallodynia, reduced tolerance, and inhibition of spinal cord neuroinflammation in male spared nerve-injured rats., (Published by Elsevier Inc.)

Background and Objective: Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of a sigma-1 receptor (σ1R) antagonist in managing neuropathic pain., Methods: A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084., Results: (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction (GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain., Conclusions: This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention., (© 2024. The Author(s).)

Competing Interests: Conflict of Interest The authors reported no conflict of interest.

Diabetic peripheral neuropathy (DPN) and diabetic osteoporosis (DOP) are conditions that significantly impact the quality of life of patients worldwide. Rehmanniae Radix Preparata, a component of traditional Chinese medicine with a history spanning thousands of years, has been utilized in the treatment of osteoporosis and diabetes. Specifically, Rehmannia glutinosa Libosch polysaccharide (RGP), a key bioactive compound of Rehmanniae Radix Preparata, has demonstrated immune-modulating properties and beneficial effects on hyperglycemia, hyperlipidemia, and vascular inflammation in diabetic mice. Despite these known actions, the precise mechanisms of RGP in addressing DOP and DPN remain unclear. Our study aimed to explore the impact of RGP on osteoporosis and peripheral neuropathic pain in diabetic mice induced by streptozotocin (STZ). The findings revealed that RGP not only improved hyperglycemia and osteoporosis in STZ-induced diabetic mice but also enhanced osteogenesis, insulin production, and nerve health. Specifically, RGP alleviated distal pain, improved nerve conduction velocity, nerve fiber integrity, and immune cell balance in the spleen. Mechanistically, RGP was found to upregulate HDAC6 mRNA expression in regulatory T cells, potentially shedding light on novel pathways for preventing DOP and DPN. These results offer promising insights for the development of new therapeutic approaches for diabetic complications., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Explore the indications for long-stay gabapentin use and elucidate the factors spurring the rapid increase in gabapentin prescribing in nursing homes (NHs)., Methods: National cross-sectional survey of NH prescribers distributed anonymously using SurveyMonkey. Sampling for convenience was obtained through crowdsourcing, leveraging collaborations with NH clinician organizations. Developed by a multidisciplinary team, pilot data/existing literature informed survey content., Results: A total of 131 surveys completed. Participants: 71% white, 52% female, 71% physicians. Off-label gabapentin prescribing was ubiquitous. Nearly every clinician used gabapentin for neuropathic pain, most for any form of pain. Many clinicians also prescribe gabapentin to moderate psychiatric symptoms and behaviors. Clinicians' prescribing was influenced by opioid, antipsychotic, and anxiolytic reduction policies because gabapentin was perceived as an unmonitored and safer alternative., Conclusions: Off-label gabapentin increases are closely linked to opioid reduction efforts as more NH clinicians utilize gabapentin as an unmonitored opioid alternative. Our results highlight, however, the less recognized significance of long-stay prescribing for psychiatric symptoms and the similar contribution of psychotropic reduction initiatives, a phenomenon warranting further scrutiny., Clinical Implications: Clinicians perceive gabapentin as safer than the drugs it is replacing. Whether this is true remains unclear; the individual- and population-level risks of increased gabapentin use are largely unknown.

Objectives: Bupropion is an atypical antidepressant that shows robust efficacy in the regulation of neuropathic pain. Citicoline is a dietary supplement which is used as a neuroprotective agent for central nervous system (CNS) disorders. The probable interaction between bupropion and citicoline on neuropathic pain was assessed in male mice., Methods: Neuropathic pain was induced by sciatic nerve ligation. Neuropathic pain was examined in nerve-ligated mice using tail-flick and hot-plate tests., Results: The results indicated that intraperitoneal (i.p.) administration of citicoline (50 and 100 mg/kg) induced an anti-nociceptive effect in nerve-ligated animals. Similarly, i.p. injection of bupropion (2.5 and 5 mg/kg) induced anti-nociceptive effects in nerve-ligated mice. Co-administration of different doses of bupropion (2.5 and 5 mg/kg) along with a low dose of citicoline (25 mg/kg) caused an anti-nociceptive effect by enhancement of tail-flick and hot plate latencies. Interestingly, there is an additive effect between bupropion and citicoline upon the induction of the anti-nociceptive effect., Conclusions: Based on these results, it can be concluded that there is an interaction between bupropion and citicoline upon induction of an anti-nociceptive effect in nerve-ligated mice.

Neuropathic pain (NP) remains one of the world's most difficult problems, and people suffering from NP have their quality of life affected to a great extent and constantly suffer from pain. Sensitization of injurious receptors, ectopic firing of afferent nerves after nerve injury, and coupling between sympathetic and sensory neurons are involved in the onset or development of NP, but the pathogenesis of NP is still not well understood. We found that the ubiquitin system is involved in the pathogenesis of NP and has a crucial role in it. The ubiquitin system can be involved in the onset or reversal of NP by affecting ion channels, cellular signal transduction, glial cells, and the regulation of non-coding RNAs. This provides new ideas for the treatment of NP. The ubiquitin system may be a new effective target for the treatment of NP. A continued, in-depth understanding of the mechanisms of the ubiquitin system involved in NP could further refine the study of analgesic targets and improve pharmacological studies., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationship., (Copyright © 2024. Published by Elsevier Masson SAS.)

Although previous studies suggest that Piezo2 regulates chronic pain in the orofacial area, few studies have reported the direct evidence of Piezo2's involvement in inflammatory and neuropathic pain in the orofacial region. In this study, we used male Sprague Dawley rats to investigate the role of the Piezo2 pathway in the development of inflammatory and neuropathic pain. The present study used interleukin (IL)-1 β -induced pronociception as an inflammatory pain model. Subcutaneous injection of IL-1 β produced significant mechanical allodynia and thermal hyperalgesia. Subcutaneous injection of a Piezo2 inhibitor significantly blocked mechanical allodynia and thermal hyperalgesia induced by subcutaneously injected IL-1 β . Furthermore, the present study also used a neuropathic pain model caused by the misplacement of a dental implant, leading to notable mechanical allodynia as a consequence of inferior alveolar nerve injury. Western blot analysis revealed increased levels of Piezo2 in the trigeminal ganglion and the trigeminal subnucleus caudalis after inferior alveolar nerve injury. Furthermore, subcutaneous and intracisternal injections of a Piezo2 inhibitor blocked neuropathic mechanical allodynia. These results suggest that the Piezo2 pathway plays a critical role in the development of inflammatory and neuropathic pain in the orofacial area. Therefore, blocking the Piezo2 pathway could be the foundation for developing new therapeutic strategies to treat orofacial pain conditions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Min-Jeong Jo et al.)

Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 50%) of chemotherapy induced peripheral neuropathy in patients. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hanna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)