生理学报最新文献

Chronic pain and pruritus are significant health challenges that pose major threats to human well-being, with existing therapeutic approaches being limited in their efficacy and scope. Electroacupuncture, as a therapy developed by combining traditional acupuncture with modern electrophysiological techniques, has emerged as a promising therapeutic modality, characterized by its low risk and excellent tolerability, and has demonstrated unique advantages in the treatment of related disorders. In recent years, the role of the endocannabinoid system in modulating pain and pruritus has garnered increasing attention as a research hotspot. This review systematically examined the composition and function of the endocannabinoid system, as well as its regulatory mechanisms in pain and pruritus signaling within the central nervous system and peripheral immune system. Additionally, we summarized the current state of research on the analgesic and itch-relieving effects of electroacupuncture through modulation of the endocannabinoid system, aiming to provide novel insights and theoretical foundations for the clinical management of pain and itch-related diseases.

This study aimed to investigate the differential roles of GluN2A and GluN2B subunits of N-methyl-D-aspartate receptor (NMDAR) in the medial prefrontal cortex (mPFC) and their downstream signaling pathways in a mouse model of chronic constrictive injury of the infraorbital nerve (CION)-induced pain and anxiety/depression-like behaviors. A mouse model of trigeminal neuropathic pain was established under CION surgery. Behavioral tests were conducted to assess mechanical thresholds and anxiety/depression-like behaviors. The protein expression levels of GluN2A, GluN2B, ERK and mTOR in the mPFC were detected by Western blot. GluN2A antagonist (PEAQX) and GluN2B antagonist (Ifenprodil) were microinjected into the mPFC to observe their behavioral effects and underlying molecular mechanisms. CION mice developed persistent pain and anxiety/depression-like behaviors, accompanied by increased GluN2B expression in the mPFC. Behavioral results showed that compared with the vehicle group, GluN2A antagonist PEAQX ameliorated anxiety/depression-like behaviors, but not pain hyperalgesia. However, GluN2B antagonist Ifenprodil significantly alleviated pain and depressive-like symptoms instead of anxiety-like behaviors. Western blot analysis revealed that PEAQX significantly increased the expression of phosphorylation of ERK1 and ERK2, while reduced the expression of both total ERK1 and total ERK2. On the other hand, Ifenprodil decreased the expression of total mTOR protein. Neither antagonist had a significant effect on phospho-mTOR levels. Taken together, our findings suggest that GluN2A and GluN2B subunits in the mPFC differentially contribute to chronic pain and anxiety/depressive-like behaviors through their respective intracellular signaling. This study provides novel insights into the mechanisms underlying chronic pain and emotional comorbidity, and offers experimental evidence for developing targeted therapeutic strategies against specific NMDAR subunits.

Migraine is a common primary headache disorder in clinical practice, and its recurrent nature severely impairs patients' quality of life. Data from the 2021 Global Burden of Disease Study indicate that migraine imposes a heavy burden on patients, their families, and society. In recent years, the association between mitochondrial dysfunction and migraine has attracted increasing attention. Studies have demonstrated that during migraine attacks, skeletal muscle cells exhibit significant mitochondrial morphological changes (such as mitochondrial swelling and cristae disruption), while platelets show mitochondrial biochemical abnormalities (e.g., reduced respiratory chain enzyme activity). Impaired energy metabolism in the brain tissue of migraine patients suggests that mitochondrial dysfunction may be involved in the pathogenesis of migraine. With rapid advances in technologies such as high-throughput sequencing and targeted sequencing, genetic variations in mitochondrial DNA (mtDNA) have gradually become a research hotspot in the etiology of migraine. Several studies have identified mtDNA genetic variations in migraine patients, which may affect the onset and progression of migraine by regulating mitochondrial energy metabolism pathways and inducing oxidative stress. This article systematically summarizes recent research progress on the correlation between migraine and mtDNA, focuses on classifying the main types and characteristics of mtDNA variations, analyzes the controversies and limitations of current studies, and outlines future research directions, thereby providing an important reference for exploring the etiology of migraine.

Persistent postsurgical pain is a major clinical concern, especially in the aging population, who represent a growing proportion of surgical patients. Although age is a known pain risk factor, the mechanisms driving age-related vulnerability to chronic postoperative pain remain poorly understood. This study aims to investigate how aging influences the resolution of postoperative pain and to elucidate the roles of microglial activation and synaptic remodeling in the spinal dorsal horn. A plantar incision model in young (3-month-old) and aged (18-month-old) male and female mice was used to mimic postoperative pain conditions. Mechanical and thermal hypersensitivity at various postoperative intervals were assessed by von Frey and Hargreaves tests. Microglial activation and inhibitory/excitatory synaptic densities in the spinal dorsal horn were evaluated using immunofluorescence and 3D reconstruction with Imaris software. On postoperative day (POD) 3, both age groups exhibited reduced pain thresholds on the ipsilateral side, along with microglial activation in the dorsal horn. On POD 7, pain thresholds in young mice had returned to baseline with no significant microglial activation, while aged mice showed sustained reduction in pain thresholds, continuous microglial activation, and significant loss of inhibitory synapses without detectable changes in excitatory synapse density. These findings are consistent across both sexes, with no sex-related differences. Collectively, these results suggest that aging is associated with persistent postoperative pain, which correlates with microglial activation and inhibitory synapse loss. These insights advance our understanding of age-related pain vulnerability and may inform the development of more effective, targeted, and age-specific therapeutic strategies to prevent or alleviate persistent postoperative pain in elderly patients.

Chronic migraine (CM) is a prevalent and highly debilitating neurological disorder. Functional magnetic resonance imaging (fMRI) studies have demonstrated associations between abnormal brain region activation and CM, yet the underlying complex neural circuitry mechanisms remain unclear. The spinal trigeminal nucleus caudalis (Sp5C) serves as the primary central hub for orofacial nociceptive input, receiving trigeminal pain signals and projecting to higher-order centers such as the thalamus. Therefore, we sought to investigate whether the Sp5C region and its associated circuits were involved in CM pathogenesis. In this study, we established a CM mouse model through repeated intraperitoneal injections of nitroglycerin (NTG). Using a combination of in vivo fiber photometry and in vitro c-Fos immunohistochemistry, we found a marked periorbital and plantar mechanical allodynia in CM mice, accompanied by increased glutamatergic neuronal activity in Sp5C. Chemogenetic manipulation of Sp5C glutamatergic neurons (Sp5C^Vglut2) bidirectionally modulated migraine-like behaviors and induced pain-related affective states, as evidenced by conditioned place preference/aversion (CPP/CPA) paradigms. Anterograde viral tracing revealed dense projections from Sp5C^Vglut2 to the subthalamic nucleus (STN), which was activated in CM mice. Optogenetic activation of the Sp5C-STN pathway similarly produced migraine-like behaviors and pain-related aversive memory in mice. Altogether, we revealed a critical role of the Sp5C^Vglut2-STN circuit in the development and modulation of CM. Our findings provide novel mechanistic insights into the central mechanisms underlying CM, establishing potential theoretical foundations for clinical diagnosis and therapeutic development.

The NLRP3 inflammasome, a pivotal effector of the innate immune system, has emerged as a critical regulator in the initiation and maintenance of chronic pain. Accumulating evidence demonstrates that NLRP3 inflammasome activation in the peripheral nervous system, particularly in dorsal root ganglia (DRG), promotes the release of pro-inflammatory mediators such as interleukin-1β (IL-1β), enhances sensory neuronal excitability, and facilitates nociceptive signal transmission and amplification. Moreover, satellite glial cells and infiltrating immune cells within the DRG contribute to the establishment of an inflammatory microenvironment, forming a neuron-glia-immune network that drives pain sensitization. In the central nervous system, activation of the NLRP3 inflammasome in microglia and astrocytes induces alterations in synaptic plasticity and central sensitization, further exacerbating the aberrant amplification of pain signals. This review summarizes recent advances in elucidating the regulatory mechanisms of the NLRP3 inflammasome in chronic pain in both peripheral and central nervous systems, providing a theoretical foundation for the development of novel analgesic strategies targeting the inflammasome.

Alcohol use disorder (AUD) is a complex chronic relapsing brain disease that poses significant threats to individual health and public healthcare systems. Hyperalgesia, an increased sensitivity to pain, has been recognized as a critical factor leading to treatment failure in AUD management. Existing pharmacotherapies inadequately alleviate pain symptoms in AUD patients, highlighting an urgent need for novel therapeutic strategies. This review systematically summarizes the multi-system neurobiological mechanisms underlying AUD-induced hyperalgesia, spanning from molecular to circuit levels, and from the central to the peripheral nervous systems. It elucidates classic pathways including neurotransmitter imbalances (e.g., enhanced glutamatergic excitation and weakened GABAergic inhibition) and glial cell-mediated neuroinflammation. This article conducts an in-depth analysis of emerging mechanisms including epigenetic regulation (DNA methylation, histone modifications, and microRNA-mediated expression control of key genes) and the gut-brain axis (where gut microbiota influence the central nervous system via metabolites), while emphasizing sex hormone mediated gender differences. Based on these insights, we propose novel intervention strategies targeting neural circuits, epigenetic modifying enzymes, and gut microbiota, offering new perspectives for clinical treatment of AUD-induced hyperalgesia, which holds significant promise for reducing relapse rates and improving patient prognosis.

Oxytocin has been found to modulate and improve pain in humans, but the mechanisms underlying these antinociceptive properties, especially in visceral hypersensitivity, are still unclear. Irritable bowel syndrome (IBS) models were established by colorectal distention in newborn rats aged 8 to 14 days, and visceral hypersensitivity was assessed using electromyogram (EMG). Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats. The protein expressions of oxytocin receptor (OTR), γ-aminobutyric acid type B1 receptor (GABAB1), and transient receptor potential vanilloid 1 (TRPV1) in the lumbosacral spinal cord regions were measured. IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression. Intrathecal oxytocin treatment not only normalized these molecular alterations (increasing GABAB1 while decreasing TRPV1) but also ameliorated visceral pain behaviors. Crucially, this therapeutic effect was fully reversed by GABAB1 inhibition, establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia. Collectively, these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.

Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies, arising from multifactorial mechanisms involving peripheral, central, and systemic pathways. Conventional analgesics, including opioids and nonsteroidal anti-inflammatory drugs, are often limited by their insufficient efficacy, tolerance, and risk of dependence. Traditional Chinese Medicine (TCM), characterized by its multi-component, multi-target, and systemic regulatory properties, has shown promising potential in cancer pain management. This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain (including nerve infiltration, dysregulation of inflammatory mediators and ion channels, central sensitization, neuro-immune crosstalk, metabolic reprogramming, and gut-brain axis impairment), as well as the analgesic effects of representative TCM agents in cancer pain management. For example, bioactive components such as tetrahydroberberine, levo-tetrahydropalmatine, and piperine exert analgesic effects, thereby improving the quality of life of patients by inhibiting inflammatory cascades, regulating neurotransmitter systems, and preserving neural integrity. Commonly used preclinical models, including bone cancer pain, pancreatic cancer pain, and chemotherapy-induced peripheral neuropathy models, are summarized for their utility in mechanistic studies and efficacy evaluations. This review also discusses the current limitations of clinical evidence, such as small sample sizes, short follow-up periods, and limited translation from animal models, alongside major challenges in standardization, mechanistic elucidation, and clinical trial design. Future directions should focus on precise pain phenotyping, integrated multi-target interventions, rigorous efficacy-safety validation, and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.

Knee osteoarthritis (KOA) represents one of the most common causes of chronic pain. The high prevalence and disability rates of KOA impose a severe burden on both individuals and society. In contrast to cutaneous pain, KOA-induced joint pain is characterized as a deep tissue pain that potentially involves distinct subgroups of peripheral sensory neurons and central processing mechanisms. Furthermore, KOA pain is closely related to locomotion activity. Impaired sensorimotor integration and pain mutually reinforce each other in KOA, forming a vicious cycle that exacerbates disease progression. In this review, we highlight the key differences between KOA pain and cutaneous pain, and the latter has been extensively studied in the pain field. We hope to offer new insights into the central mechanisms and development of new treatment strategies for KOA based on the interactions between impaired sensorimotor integration and chronic joint pain.