Migraine is a very common chronic neurological disorder associated with severe disability and significant social burden worldwide. Beyond recurrent headache attacks, increasing evidence indicates that migraine often coexists with a broad range of systemic disorders, forming complex and often bidirectional relationships. These overlapping conditions complicate clinical management and suggest the presence of shared pathophysiological mechanisms extending beyond the central nervous system. Epidemiological studies have consistently shown strong associations between migraine and multiple comorbidities, including epilepsy, psychiatric disorders, sleep disturbances, cardio-cerebrovascular diseases, multiple sclerosis, asthma, other chronic pain syndromes, gastrointestinal disorders, and metabolic‒endocrine abnormalities. The presence of these conditions is generally associated with increased disease severity, higher rates of migraine chronification, poorer treatment responses, and increased healthcare utilization. Emerging mechanistic evidence indicates that migraine and its comorbidities share common biological pathways, including dysregulation of neurovascular signaling, neuroinflammation, central sensitization, alteration in autonomic nervous system and brain function, and disturbances in immune and metabolic homeostasis. Importantly, the presence of comorbid conditions may affect the efficacy, tolerance and safety of treatment, highlighting the limitations of symptom-oriented treatment strategies that fail to address these shared mechanisms. This review synthesizes current evidence on the epidemiological associations, shared pathophysiological mechanisms, and clinical implications of migraine and its common comorbidities. By elucidating these interrelated pathways, we aim to inform the development of comprehensive, personalized management strategies that transcend symptom-oriented treatment towards mechanism-based, comorbidity-informed approaches. Future research should prioritize the identification of biomarkers and the refinement of patient stratification tools to facilitate precision medicine in migraine and its associated conditions.

Migraine is a common, disabling neurological disorder driven by neurovascular and neuroinflammatory mechanisms. Although calcitonin gene–related peptide (CGRP)-targeted and serotonergic drugs have improved treatment, many patients still respond inadequately or experience side effects. Acupuncture is widely used as a non-pharmacological alternative, yet its mechanistic basis lacks systematic integration. Accumulating clinical and experimental evidence suggest that acupuncture effectively reduces migraine frequency, pain intensity, and disability, with sustained preventive benefits. Neuroimaging studies reveal that acupuncture modulates key brain regions and networks involved in pain perception, emotional regulation, and descending pain control, including the default mode, salience, and sensorimotor networks. At the molecular level, preclinical evidence indicates that acupuncture may modulate CGRP signaling, serotonergic neurotransmission, neuronal excitability, and inflammatory pathways, thereby attenuating central sensitization and neuroimmune activation. Emerging evidence further suggests that acupuncture affects hypothalamic metabolic pathways involving glucagon-like peptide-1 (GLP-1) and orexin. Given that these neuropeptides are also implicated in the pathogenesis of migraines, this finding may offer a potential mechanistic perspective on how acupuncture alleviates this condition. These findings support a multi-level regulatory role of acupuncture that extends beyond symptomatic analgesia. Acupuncture is supported as a preventive therapy for select migraine patients, but mechanistic evidence remains heterogeneous and mostly associative or preclinical. While a multilevel framework might link acupuncture-evoked brain, molecular, and homeostatic changes, direct validation in migraine is needed. Future work should prioritize standardized interventions, credible sham controls, longitudinal neuroimaging, and integrated molecular readouts to elucidate response mechanisms and predictive biomarkers. Not applicable.

Migraine is a chronic neurological disorder characterized by severe headache, nausea, and sensitivity to light and sound, affecting approximately 1 billion people globally. Despite advances in understanding migraine pathophysiology, particularly with the emergence of CGRP-targeted therapies, the mechanisms underlying neuroinflammation and glial contributions remain poorly understood. Current treatments are effective for a subset of patients, yet they don’t tackle the fundamental neurogenic and neuroinflammatory processes that fuel chronic migraine, especially the pathophysiological aspects contributed by glial cells. This review integrates recent preclinical and clinical evidence to elucidate how diverse glial cells, including central glia (astrocytes, microglia and oligodendrocytes) and peripheral glia (Schwann cells, satellite glial cells), coordinate the neuroinflammation associated with migraine. Evidence shows that astrocytes and microglia are essential to both cortical spreading depolarization (CSD) and mediating the inflammatory cascades that maintain chronic pain. Oligodendrocytes, though less studied, are predicted to affect neuronal excitability and energy metabolism, while Schwann cells and satellite glial cells mediate peripheral nociceptive signaling through their interactions with neural and immune elements. New therapeutic strategies have been put forward. These include targeting glial-specific signaling pathways and employing advanced drug delivery systems such as viral vectors and nanoparticles to improve treatment effectiveness. Glial cells are pivotal regulators of migraine-associated neuroinflammation. This review underscores their critical role in migraine pathophysiology and highlights glial-targeted therapies as a promising direction for future research and treatment development.

Migraine is a common, disabling brain disorder that affects about 1 billion people worldwide and disproportionately burdens women and working-age adults. Once viewed mainly as a vascular headache, migraine is now understood as a heterogeneous neurobiological syndrome arising from interactions among genetic susceptibility, hormonal influences, environmental exposures, and cortical, brainstem, trigeminovascular, and neuroinflammatory networks. Although calcitonin gene-related peptide (CGRP)-pathway therapies, gepants, and neuromodulation have transformed care, major gaps remain in disease stratification, prevention of chronification and management of special populations. Here, we review recent evidence on global and regional epidemiology, sex-specific and environmental risk factors, and the transition from episodic to chronic migraine. We then examine current mechanistic models, focusing on cortical spreading depolarization, trigeminovascular signaling, CGRP biology, neurogenic inflammation, glial activation, and brain network dysfunction. We also assess acute and preventive treatment strategies, including ditans, gepants, monoclonal antibodies, and onabotulinumtoxinA, and discuss persistent challenges in pediatric, geriatric, and pregnancy-associated migraine care. By integrating population, mechanistic and therapeutic perspectives, this review reframes migraine as a stratified brain network disorder rather than a uniform vascular pain syndrome. This synthesis highlights priorities for biomarker development, precision medicine, and more equitable implementation of effective migraine care.

The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. However, the underlying molecular mechanisms remain unclear. This study shows a SET-domain bifurcated histone lysine methyltransferase, SETDB2, in trigeminal ganglion (TG) neurons as a key mediator of migraine-like pain. In a mouse model of chronic migraine induced by nitroglycerin (NTG), SETDB2 is significantly upregulated in TG neurons, a finding mirrored in cerebrospinal fluid from patients with migraine. Reversing this upregulation reduces levels of the repressive histone mark H3K9me3 and alleviates migraine-like pain behaviors in mice, whereas mimicking it induces hypersensitivity. Mechanistically, SETDB2 upregulation impedes transcription factor KLF4 from binding to the promoter of the insulin-degrading enzyme (Ide) gene, thereby suppressing IDE expression and impairing degradation of calcitonin-gene-related peptide (CGRP) in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present therapeutic opportunities for treating migraine.

Nerve injury-induced reprogramming of sensory neuron gene expression is a key driver of neuropathic pain. However, the transcriptional networks that orchestrate this maladaptive plasticity remain largely undefined. Here, we identify the transcriptional repressor ZBTB18 as a critical regulator of this pathogenic process. Peripheral nerve injury markedly downregulated the level of ZBTB18 in the injured trigeminal ganglion (TG) of rats. Restoring ZBTB18 expression reverses injury-induced mechanical allodynia, while its knockdown in naive TG neurons is sufficient to recapitulate neuropathic pain symptoms. Mechanistically, ZBTB18 directly represses Clic1 transcription by engaging a specific silencer element within its promoter. This repression is achieved through the recruitment of the nucleosome remodeling and deacetylase (NuRD) complex, an interaction mediated by the ZBTB18 BTB domain and the chromodomain helicase DNA-binding protein 4 (CHD4). Disruption of this recruitment abrogates histone H3K27ac deacetylation at the Clic1 promoter, enhancing RNA polymerase II occupancy and driving Clic1 expression. Consequently, nerve injury-induced loss of ZBTB18 relieves this epigenetic brake, leading to CLIC1 upregulation, increased chloride channel activity, and hyperexcitability of TG neurons that underlies mechanical hypersensitivity. In summary, these findings reveal a novel ZBTB18/NuRD/CLIC1 epigenetic axis in neuropathic pain and highlight this transcriptional pathway as a potential target for therapeutic intervention.

Herein, we show a molecular pathway driven by an evolutionarily conserved microRNA (miRNA) in sensory neurons to control neuropathic pain. By employing high-throughput sequencing analysis, we find that miRNA-323-3p (miR-323-3p) exhibits the most significant upregulation in injured trigeminal ganglia (TGs). Local inhibition of miR-323-3p in injured TGs suppresses established trigeminal neuropathic pain but has no effect on inflammatory pain. Mechanistically, nerve injury upregulates the protein expression of protein arginine methyltransferase 2 (PRMT2), which promotes asymmetric dimethylation of H3R8, thereby facilitating the binding of the transcription factor forkhead box A2 (FOXA2) to the miR-323-3p promoter and resulting in the upregulation of miR-323-3p expression. Furthermore, the increased miR-323-3p expression induces significant reductions in Kv2.1 protein expression and channel currents, resulting in TG neuronal hyperexcitability. Conversely, the downregulation of miR-323-3p in injured TGs restores the decreased Kv2.1 expression and attenuates nerve-injury-induced mechanical hypersensitivity. The PRMT2/FOXA2/miR-323-3p/Kv2.1 signaling axis in sensory neurons may offer therapeutic targets in neuropathic pain management.

Although the therapeutic potential of microRNA-mediated gene regulation has been investigated, its precise functional regulatory mechanism in neuropathic pain remains incompletely understood. In this study, we elucidate that miR-216a-3p serves as a critical noncoding RNA involved in the modulation of trigeminal-mediated neuropathic pain. By conducting RNA-seq and qPCR analysis, we observed a notable decrease of miR-216a-3p in the injured trigeminal ganglia (TG) of male rats. Intra-TG administration of miR-216a-3p agomir or lentiviral-mediated overexpression of miR-216a-3p specifically in sensory neurons of injured TGs alleviated established neuropathic pain behaviors, while downregulation of miR-216a-3p (pharmacologically or genetically) in naive rats induced pain behaviors. Moreover, nerve injury significantly elevated the histone H3 lysine-27 (H3K27) trimethylation (H3K27me3) levels in the ipsilateral TG, thereby suppressing the SRY-box TF 10 (SOX10) binding to the miR-216a-3p promoter and resulting in the reduction of miR-216a-3p. Inhibiting the enzymes responsible for catalyzing H3K27me3 restored the nerve injury-induced reduction in miR-216a-3p expression and markedly ameliorated neuropathic pain behaviors. Furthermore, miR-216a-3p targeted stromal interaction molecule 1 (STIM1), and the decreased miR-216a-3p associated with neuropathic pain caused a significant upregulation in the protein abundance of STIM1. Conversely, overexpression of miR-216a-3p in the injured TG suppressed the upregulation of STIM1 expression and reversed the mechanical allodynia. Together, the mechanistic understanding of H3K27me3-dependent SOX10/miR-216a-3p/STIM1 signaling axial in sensory neurons may facilitate the discovery of innovative therapeutic strategies for neuropathic pain management.

Headache disorders, including migraine, tension-type headache, and cluster headache, are among the most prevalent and disabling neurological conditions. Although genetic factors contribute to their pathogenesis, they fail to fully account for their clinical heterogeneity, episodic nature, and varied treatment responses. This review synthesizes current evidence on the role of epigenetic mechanisms—including DNA methylation, histone modifications, non-coding RNAs, and RNA modifications—in the pathophysiology of headache disorders. Evidence from both human studies and animal models demonstrates that epigenetic mechanisms serve as a dynamic interface between genetic predisposition and environmental triggers. Key findings indicate that stress, sleep disturbances, and hormonal fluctuations can induce specific alterations in DNA methylation and histone acetylation within genes critical to the trigeminovascular system and hypothalamic function, thereby modulating central sensitization and attack susceptibility. Furthermore, distinct profiles of non-coding RNAs have been identified in patient biofluids, correlating with disease state and treatment outcomes, highlighting their potential as clinical biomarkers. The review also synthesizes emerging evidence on how these mechanisms collectively influence cortical spreading depression, neurotransmitter release, and neuroimmune signaling, providing a mechanistic framework for disorder progression and chronification. Importantly, we explore the therapeutic promise of epigenetic drugs and epigenome-editing technologies that are moving from preclinical validation toward early-phase clinical trials for headache management. This review advances the understanding of headache disorders by highlighting a dynamic, modifiable layer of regulation at the gene-environment interface. As a promising translational frontier, epigenetics opens new paths for precision medicine and the creation of targeted therapies.

BACKGROUND:Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear. METHODS:Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca2+ channels (T-type channels). RESULTS:IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2. CONCLUSION:Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management.

AimThe impact of Pleistocene climate fluctuations on the biogeographical history of aquatic species has been a topic of enduring debate. This issue poses particular challenges for parapatric closely related species, especially those situated in transition zones where species assemblages occur between distinct zoogeographic boundaries.LocationEastern China.TaxonFive closely related Sinopotamon species and subspecies, S. shensiense, S. honanense, S. y. yangtsekiense, S. y. shanxianense, and S. y. tongbaiense.MethodsThese parapatric Sinopotamon species and subspecies, distributed along the boundary between the Palaearctic and Oriental realms in eastern China, offer an ideal model for addressing these challenges. We explored the biogeographic history of these species by conducting a comparative phylogeographic analysis using nine microsatellite loci and two mitochondrial DNA sequences, combined with morphological variation and fine-tuned ecological niche modelling.ResultsOur phylogeographic analyses consistently revealed two well-supported clades: clade A, for S. y. yangtsekiense, and clade B, which includes other species showing polyphyletic patterning and significant gene introgression. The Nanyang Basin and surrounding mountains regions (NBSM) was identified as a critical shared refuge and hybrid zone, facilitating interspecific introgression through at least two putative hybridisation events. During the Late Pleistocene glacial cycles, introgressive hybridisation of these species occurred in the NBSM, followed by rapid expansion and colonisation of heterogenous habitats during interglacial cycles, with dispersal corridors largely aligning with the local river system. In particular, the diffusion corridor of S. honanense significantly disrupted the continuous distribution of S. y. shanxianense and S. y. tongbaiense, indicating that S. honanense has replaced S. y. shanxianense and S. y. tongbaiense in the NYSM and caused a disruption in its distribution.Main ConclusionsThe biogeographic histories of the species in clade B are consistent with a mixing-isolation-mixing model, which suggests that populations experienced repeated introgressive hybridisation during glacial periods and regional habitat isolation during interglacial periods. Our findings represent a classic case of fine tracking biogeographical scenarios in parapatric species and provide unprecedented insights into the evolutionary radiation of the freshwater fauna that occupies zoogeographic boundaries.

Chronic pain represents a prevalent and costly medical challenge globally. Nicotinic acetylcholine receptors (nAChRs), one type of ligand-gated ion channels found extensively in both the central and peripheral nervous systems, have emerged as promising therapeutic targets for chronic pain. Although there are currently no FDA-approved analgesics specifically targeting nAChRs, accumulating preclinical and clinical evidence suggest that selective ligands for alpha 7 (α7) nAChRs show potential for treating chronic pain, boasting a reduced incidence of side effects compared with other nicotinic receptor types. The recent structural resolution of human α7 nAChRs has confirmed their negative association with heightened pain, providing a valuable foundation for the development of targeted medications. This review presents a comprehensive overview, encompassing insights into the roles of α7 nAChRs derived from structural and functional studies, recent advancements in pharmacology, and investigations into their involvement in the pathophysiology of chronic pain. Moreover, the review addresses the variability in analgesic effects based on the type of receptor agonist and highlights the current research limitations. As such, this review offers potential therapeutic approaches for the development of innovative strategies for chronic pain management.

The N6-methyladenosine (m 6 A) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement in modulating neuropathic pain is still poorly understood. In this study, we elucidate a functional role of the m 6 A demethylase alkylation repair homolog 5 (ALKBH5) in modulating trigeminal-mediated neuropathic pain. Peripheral nerve injury selectively upregulated the expression level of ALKBH5 in the injured trigeminal ganglion (TG) of rats. Blocking this upregulation in injured TGs alleviated trigeminal neuropathic pain, while mimicking the upregulation of ALKBH5 in intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation induced by nerve injury increases histone H3 lysine 27 acetylation (H3K27ac), facilitating the binding of the transcription factor forkhead box protein D3 (FOXD3) to the Alkbh5 promoter and promoting Alkbh5 transcription. The increased ALKBH5 erases m 6 A sites in Htr3a messenger RNA (mRNA), resulting in an inability of YT521-B homology domain 2 (YTHDF2) to bind to Htr3a mRNA, thus causing an increase in 5-HT3A protein expression and 5-HT3 channel currents. Conversely, blocking the increased expression of ALKBH5 in the injured TG destabilizes nerve injury–induced 5-HT3A upregulation and reverses mechanical allodynia, and the effect can be blocked by 5-HT3A knockdown. Together, FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain through m 6 A-dependent stabilization of Htr3a mRNA in TG neurons. This mechanistic understanding may advance the discovery of new therapeutic targets for neuropathic pain management.

新医科背景下虚拟教研室的建设是落实国家"双一流"专业建设目标、提升高校教学水平和人才培养质量的重要举措.苏州大学医学机能学团队积极响应国家需要与时代呼唤,与贵州医科大学和右江民族医学院联合申报跨校医学机能学虚拟教研室建设点,成为首批江苏省虚拟教研室建设培育点.教研室结合新医科人才培养要求,对教学理念、课程体系、教学内容和教学方法进行重构,为新医科背景下医学基层教学组织的构建与运行提供了有益参考.

Trace amines, such as tyramine, are endogenous amino acid metabolites that have been hypothesized to promote headache. However, the underlying cellular and molecular mechanisms remain unknown. Using patch-clamp recording, immunostaining, molecular biological approaches and behaviour tests, we elucidated a critically functional role of tyramine in regulating membrane excitability and pain sensitivity by manipulating Kv1.4 channels in trigeminal ganglion (TG) neurons. Application of tyramine to TG neurons decreased the A-type K+ current (IA) in a manner dependent on trace amine-associated receptor 1 (TAAR1). Either siRNA knockdown of Gαo or chemical inhibition of βγ subunit (Gβγ) signaling abrogated the response to tyramine. Antagonism of protein kinase C (PKC) prevented the tyramine-induced IA response, while inhibition of conventional PKC isoforms or protein kinase A elicited no such effect. Tyramine increased the membrane abundance of PKCθ in TG neurons, and either pharmacological or genetic inhibition of PKCθ blocked the TAAR1-mediated IA decrease. Furthermore, PKCθ-dependent IA suppression was mediated by Kv1.4 channels. Knockdown of Kv1.4 abrogated the TAAR1-induced IA decrease, neuronal hyperexcitability, and pain hypersensitivity. In a mouse model of migraine induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus, blockade of TAAR1 signaling attenuated mechanical allodynia; this effect was occluded by lentiviral overexpression of Kv1.4 in TG neurons. These results suggest that tyramine induces Kv1.4-mediated IA suppression through stimulation of TAAR1 coupled to the Gβγ-dependent PKCθ signaling cascade, thereby enhancing TG neuronal excitability and mechanical pain sensitivity. Insight into TAAR1 signaling in sensory neurons provides attractive targets for the treatment of headache disorders such as migraine.

Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of β-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment.

偏头痛是一种原发性头痛,临床表现为反复发作,单侧或双侧搏动样疼痛,已成为第七大致残疾病.近年来偏头痛病人数量急剧上升,但尚未有特异性靶向药物或者有效的临床治疗方法,全球约有15%的人受偏头痛的困扰.理想的动物模型可以在很大程度上模拟偏头痛的生理病理学发病机制,极大地推动了对偏头痛的研究进展.本文将从理论依据、造模方法、观测指标、模型特点以及研究应用等方面对常用的偏头痛动物模型进行总结与讨论,以期为偏头痛的发病机制相关研究的动物模型选择提供参考.

Adipokines, including adiponectin, are implicated in nociceptive pain; however, the underlying cellular and molecular mechanisms remain unknown. Using electrophysiological recording, immunostaining, molecular biological approaches and animal behaviour tests, we elucidated a pivotal role of adiponectin in regulating membrane excitability and pain sensitivity by manipulating Cav3.2 channels in trigeminal ganglion (TG) neurons. Adiponectin enhanced T-type Ca2+ channel currents (IT) in TG neurons through the activation of adiponectin receptor 1 (adipoR1) but independently of heterotrimeric G protein-mediated signaling. Coimmunoprecipitation revealed a physical association between AdipoR1 and casein kinase II alpha-subunits (CK2α) in the TG, and inhibiting CK2 activity by chemical inhibitor or siRNA targeting CK2α prevented the adiponectin-induced IT response. Adiponectin significantly activated protein kinase C (PKC), and this effect was abrogated by CK2α knockdown. Adiponectin increased the membrane abundance of PKC beta1 (PKCβ1). Blocking PKCβ1 pharmacologically or genetically abrogated the adiponectin-induced IT increase. In heterologous expression systems, activation of adipoR1 induced a selective enhancement of Cav3.2 channel currents, dependent on PKCβ1 signaling. Functionally, adiponectin increased TG neuronal excitability and induced mechanical pain hypersensitivity, both attenuated by T-type channel blockade. In a trigeminal neuralgia model induced by chronic constriction injury of infraorbital nerve, blockade of adipoR1 signaling suppressed mechanical allodynia, which was prevented by silencing Cav3.2. Our study elucidates a novel signaling cascade wherein adiponectin stimulates TG Cav3.2 channels via adipoR1 coupled to a novel CK2α-dependent PKCβ1. This process induces neuronal hyperexcitability and pain hypersensitivity. Insight into adipoR-Cav3.2 signaling in sensory neurons provides attractive targets for pain treatment.

Background: Interleukin-33 (IL-33) has been implicated in nociceptive pain behaviors. However, the underlying molecular and cellular mechanisms remain unclear. Methods: Using electrophysiological recording, immunoblot analysis, immunofluorescence labeling, reverse transcription-PCR, siRNA-mediated knockdown approach and behavior tests, we determined the role of IL-33 in regulating sensory neuronal excitability and pain sensitivity mediated by A-type K+ channels. Results: IL-33 decreased A-type transient outward K+ currents (IA) in small-sized DRG neurons in a concentration-dependent manner, whereas the delayed rectifier currents (IDR) remained unaffected. This IL-33-induced IA decrease was dependent on suppression of the tumorigenicity 2 (ST2) receptor and was associated with a hyperpolarizing shift in the steady-state inactivation. Antagonism of Syk abrogated the IL-33-induced IA response, while inhibition of JAK2 and PKA elicited no such effect. Exposure of DRG cells to IL-33 increased the activity of Akt, but surprisingly, neither Akt nor PI3K influenced the IL-33-induced IA response. IL-33 increased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK). Chemical inhibition of p38 and genetic siRNA knockdown of p38 beta (p38β), but not p38α, abrogated the IA response induced by IL-33. Moreover, IL-33 increased neuronal excitability of DRG neurons and facilitated peripheral pain sensitivity in mice; both of these effects were occluded by IA blockade. Conclusions: Our present study reveals a novel mechanism by which IL-33/ST2 suppresses IA via a Syk-dependent p38β signaling pathway. This mechanism thereby increases DRG neuronal excitability and pain sensitivity in mice. Targeting IL-33/ST2-mediated p38β signaling may represent a therapeutic approach to ameliorate pain behaviors.