Dual activation of 5-HT1A and μ-opioid receptors mediates dezocine's antidepressant effects in mice with comorbid pain and depression.

Activating the vlPAG-LC neural pathway alleviates neuropathic pain and comorbid anxiety-like behaviors through distinct projections.

Electroacupuncture alleviates neuropathic pain and long-term cognitive impairment via the rACC-vlPAG neural circuit.

Brain-enriched guanylate kinase-associated protein in the spinal dorsal horn regulates mechanical allodynia in male mouse neuropathic and inflammatory pain model.

Hypoactivity of the prelimbic cortex projecting to the lateral entorhinal cortex contributes to neuropathic pain-induced object recognition memory impairment in mice.

Current treatment options for acute and chronic pain provide limited efficacy and safety. There is an urgent need to develop drugs with new, non-opioid treatment strategies that produce fewer adverse consequences. Preclinical evidence across multiple models of acute and chronic pain demonstrate that (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a nonhallucinogenic metabolite of ketamine, promotes potent and long-lasting analgesic effects. This review summarizes the growing evidence for the analgesic action of (2R,6R)-HNK in rodent models of acute and chronic pain. (2R,6R)-HNK produces antinociceptive effects in studies using standard tests for acute pain such as the hot plate test, although not in all studies, as well as reversal of mechanical hypersensitivity in models of acute pain like the carrageenan model (inflammatory pain). However, the most consistent anti-allodynic effects are seen in animal models aimed at mimicking chronic pain conditions, such as models of neuropathic pain (Spared Nerve Injury and Chemotherapy-induced peripheral neuropathy), low-back pain (disc puncture), complex regional pain syndrome type-1 (tibial fracture) and chronic primary pain (low-frequency percutaneous electrical nerve stimulation). Unlike ketamine, doses of (2R,6R)-HNK that counteract pain hypersensitivity do not cause sedation, dissociation, or sustain self-administration associated with abuse liability. Furthermore, distinct pharmacological effects of (2R,6R)-HNK, longer functional duration of action, non-opioid-mediated analgesia, and glutamatergic-mediated mechanisms, may distinguish (2R,6R)-HNK from ketamine and other analgesic drugs and contribute to the treatment of acute and chronic pain.

The psychedelic psilocybin may have lasting therapeutic effects for patients with chronic pain syndromes. Some preclinical data suggest these putative benefits derive from direct analgesic effects; however, this possibility has not been comprehensively tested in preclinical models. Here, we evaluated the analgesic properties of a single exposure to psilocybin at acute and chronic time points in Complete Freund's Adjuvant-induced inflammatory pain, spared nerve injury model of neuropathic pain, and acid-induced muscle pain. Across these models, we tested a range of doses (0.3, 2, and 10 mg/kg i.p.) in male and female mice using multiple behavioral assays evaluating sensory aspects (von Frey, cold plate, Hargreaves, thermal place preference, and muscle withdrawal threshold) and functional aspects of pain (marble burying). We further tested the effects of psilocybin on the affective dimension of pain in a surgical model of acute pain (mouse grimace scale). Except for cold sensitivity, we found no effect of psilocybin across pain models, behavioral assays, drug doses, or sex. The apparent reduction in cold sensitivity may be explained by profound hypothermia induced by psilocybin rather than true analgesia.

Amygdalar Calcitonin Gene-Related Peptide Driven Effects of Cold Sensitivity Induced by Peripheral Neuropathy in Mice.

Contribution of transmembrane channel-like (TMC) proteins 3, 5 and 7 to pain and itch processing.

Red nucleus IL-15 facilitates the development of neuropathic pain in male rats by inducing inflammatory factors: implying the involvement of NF-κB and p38 MAPK.

G protein-coupled receptor 17 promotes neuropathic pain in male mice by upregulating spinal NMDAR subunit expression.

NLRP10 ablation alleviates neuropathic pain by inhibiting excessive NIX/LC3-dependent mitophagy in the spinal cord.

Novel hybrid peptide BNT12 displays potent antinociception with limited opioid-like side effects at the spinal level.

Involvement of substance P/NK1 receptor system in central sensitization in chronic pain.

Early intervention in neuropathic pain can effectively delay its chronicity. Sigma non-opioid intracellular receptor 1 (SIGMAR1) is upregulated in the spinal dorsal horn during the development of spared nerve injury (SNI)-induced neuropathic pain. Methylated RNA immunoprecipitation confirmed that the SIGMAR1 upregulation was driven by mRNA N6-methyladenosine (m6A) modification. Intrathecal injection of the SIGMAR1 antagonist or siRNA effectively alleviated mechanical allodynia during the development of neuropathic pain. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and co-immunoprecipitation experiments revealed that SIGMAR1 directly binds to neuronal pentraxin-1 (NPTX1), promoting its ubiquitin-proteasome degradation. Intraspinal injection of adeno-associated virus (AAV) to specifically overexpress NPTX1 in neurons alleviates SNI-induced neuropathic pain, whereas NPTX1 knockdown reduces the mechanical pain threshold in naive male mice. Furthermore, bioinformatics predicts that NPTX1 binds the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). Downregulation of NPTX1 promoted AMPAR membrane trafficking and central sensitization. Collectively, SIGMAR1, a potential therapeutic target for early-stage neuropathic pain, promotes AMPAR-mediated hyperexcitability of nociceptive neurons through interacting with NPTX1 in male mice.

PurposePyroptosis, a programmed inflammatory cell death mechanism, plays a significant role in neuropathic pain (NP) pathogenesis. However, the specific pyroptosis-related genes (PRGs) driving NP development remain poorly understood. This study employs systematic approaches to identify and validate PRGs, aiming to delineate their mechanistic contributions to NP progression.MethodsTo elucidate pyroptosis-related genes (PRGs) in neuropathic pain pathogenesis, we first performed integrated bioinformatics analysis of the GSE236754 dataset, revealing differentially expressed PRGs in the spinal cord dorsal horn of spared nerve injury (SNI) rats. Subsequent functional enrichment analyses coupled with protein-protein interaction network construction delineated pathway convergences among identified PRGs. Experimental validation utilizing SNI rat model, Western blot and immunofluorescence quantification confirmed protein expression patterns, and immunofluorescence mapping determined cellular localization collectively. Statistical analyses via ANOVA method.ResultsBioinformatics screening identified 11 candidate PRGs in the SNI model, particularly highlighting Nlrc4 and Nlrp3 as the most upregulated targets. Gene Ontology (GO) analysis demonstrated significant enrichment in three domains, pyroptosis regulation, inflammasome complex assembly, and cysteine-type endopeptidase activity associated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis specifically identified the “NOD-like receptor signaling pathway” as significantly enriched. Gene Set Enrichment Analysis (GSEA) further corroborated these findings. Behavioral quantification showed progressive mechanical hypersensitivity, with mechanical pain and cold pain reaching maximal sensitivity at day 7 post-injury (p<0.001). Western blot detected synchronized elevation of NLRP3 and NLRC4 inflammasome components and downstream effectors across the observation window (all p<0.05). Immunofluorescence analysis demonstrated a time-dependent increase in the expression of GSDMD-N, the pyroptotic-executing protein, a trend consistent with the findings from behavioral tests and Western blot analysis (p<0.05). And cellular localization analysis revealed neuron-predominant accumulation of GSDMD-N.ConclusionWe identified 11 potential biomarkers for NP. Our data conclusively show that SNI induced NLRP3/NLRC4 inflammasome activation and neuronal pyroptosis in the rat spinal cord.

The transmission of pain signals through the spinal cord can cause structural and functional changes in the brain, which may contribute to diverse symptoms. Since the early 19th century, researchers have been studying hemispheric asymmetries in the brain and their effects across different species. However, it remains unclear whether pain-related emotional and cognitive changes are differently affected by left- and right-sided pain. To address this question, we conducted a study comparing the performance of chronic neuropathic mice with left or right spared nerve injury (SNI) in various behavioral tests. We evaluated their behaviors in the open field (OF), Y-maze, novel object recognition, and fear conditioning tests, and compared their performance to that of sham mice. Compared with sham mice, SNI mice manifested mechanical allodynia. In the OF test, SNI-L mice showed an increased anxiety-like profile compared to the other groups. Both left- and right- sided SNI mice showed cognitive deficits to a similar degree in memory tasks. Our results revealed that unilateral chronic neuropathic pain differentially affected anxiety condition, but not pain threshold and cognitive function.

Neuropathic pain (NP) is a chronic and disabling condition resulting from injury or disease of the somatosensory system. Characterized by sensory disturbances such as allodynia, hyperalgesia, and spontaneous pain, NP remains a major clinical challenge due to the limited efficacy and significant side effects of conventional pharmacological treatments. In recent years, photobiomodulation therapy (PBMT), also referred to as low-level laser therapy (LLLT), has emerged as a promising non-pharmacological strategy for managing NP. PBMT involves the application of red or near-infrared light to biological tissues, triggering a range of photochemical and photophysical responses that enhance mitochondrial function, reduce oxidative stress, modulate inflammation, and support neural repair. This review provides a comprehensive synthesis of the current evidence on PBMT for NP, integrating mechanistic insights with preclinical findings. We discuss the biological underpinnings of PBMT, including mitochondrial activation via cytochrome c oxidase, modulation of cytokines and oxidative stress markers, and upregulation of neurotrophic factors such as BDNF. Preclinical studies in well-established NP models (e.g., chronic constriction injury, spared nerve injury, diabetic neuropathy) demonstrate consistent analgesic effects and neuroprotective outcomes following both local and remote/systemic PBMT applications. We also highlight key limitations and knowledge gaps in the field, including the need for standardized protocols, greater exploration of remote PBMT strategies, and improved consideration of sex-based responses. Finally, we outline future directions, such as integration with multimodal therapies, personalized dosimetry, and the development of wearable and transcranial PBMT technologies. Together, the existing body of evidence supports PBMT as a safe and potentially effective tool for NP management, while underscoring the need for more rigorous and translational research.

Neuropathic pain is characterized by hyperalgesia, allodynia or spontaneous pain arising from lesions or pathology in the somatosensory nervous system. Multiple mechanisms contribute to this pain following peripheral nerve and spinal cord injuries. Evidence shows that injury-induced changes in dendritic spine morphology in the dorsal horn may contribute to neuropathic pain presentation. Dendritic spines, critical postsynaptic structures for synaptic transmission, undergo remodelling from filopodia-like structures to mature, mushroom-shaped spines in nociceptive spinal cord regions after injury. Recent evidence indicates that peripheral nerve and spinal cord injuries affect local tissues and also lead to pathology in supraspinal brain regions. Interestingly, different injuries appear to target specific brain regions, potentially causing corresponding remodelling of dendritic spines. To investigate this, we examined whether spared nerve injury, as a peripheral nerve injury model, and spinal cord injury induce morphological changes in dendritic spines in different brain regions and whether systemic administration of mesenchymal stem cells could alleviate neuropathic pain by altering dendritic spine morphology. Our results demonstrate that both injuries induce significant morphological changes in dendritic spines in the brain and spinal cord. Specifically, the peripheral nerve injury model increases the density of mushroom-shaped spines in superficial Lamina II of the dorsal horn, whereas spinal cord injury induces similar changes in deeper Lamina V. In the brain, the peripheral nerve injury model showed increased mushroom-shaped spines in the sensory cortex and ventral posterior complex of the thalamus. In contrast, the spinal cord injury model showed these changes primarily in the thalamic intralaminar nuclei. Infused mesenchymal stem cells partially alleviated neuropathic pain in both models and reduced the density of mushroom-shaped spines in the respective affected regions. Gene expression analysis of cytoskeletal genes related to actin associated with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AKAP5, ACTR2, and SORBS2) revealed upregulation of these genes in the sensory cortex (in the peripheral nerve injury model) and the thalamus (in the spinal cord injury model). Mesenchymal stem cells suppressed these upregulations, which were associated with reduced neuropathic pain. These findings suggest that infused mesenchymal stem cells can protect against the abnormal remodelling of dendritic spines, thereby contributing to pain alleviation regardless of injury type or affected region. The systemic administration of mesenchymal stem cells thus offers a promising therapeutic approach for treating multiple neuropathic pain conditions through structural and molecular alterations in dendritic spines.

Differential Cortico-Thalamic reorganization in Opioid-Induced hyperalgesia and neuropathic pain male rats.