BACKGROUND AND PURPOSE:Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, involved in neuronal development and neurodegenerative diseases, regulates pain. Whereas its contribution to pain processing within nociceptors is well established, but within dorsal horn neurons remains poorly understood. EXPERIMENTAL APPROACH:We used behaviour, electrophysiology, western blot and immunohistochemistry in the trigeminal ganglion (TG) and medullary dorsal horn (MDH) of male and female rats. KEY RESULTS:In naïve animals, intracisternal roscovitine (seliciclib), a CDK5 inhibitor, suppresses selectively noxious-evoked responses of MDH wide dynamic range (WDR) neurons and leaves the windup phenomenon unchanged, suggesting that CDK5 signalling within TG, but not MDH, regulates nociceptive pain. Under inflammatory conditions, roscovitine prevents the facial spontaneous pain-like behaviour, and static and dynamic secondary mechanical hypersensitivities in both sexes and the sensitization of MDH WDR neurons. But it cannot reverse them. Conversely, roscovitine reduces the neuropathic mechanical hypersensitivities. Therefore, CDK5 signalling within MDH is differently involved in chronic pain, contributing to the maintenance of neuropathic pain but only the initiation of inflammatory pain, in both sexes. Interestingly, whereas p35, p25 and pERK1/2 MDH expressions increase under inflammatory and neuropathic conditions, CDK5 expression only enhances under neuropathic ones. Finally, p35 MDH expression strongly increases following inflammatory pain, occurring in ~70-80% of neurons and also in astrocytes and microglia. CONCLUSION AND IMPLICATIONS:MDH CDK5-p35 specifically regulates, though differently, inflammatory and neuropathic pain, making it an attractive target for the development of long-lasting analgesics in both sexes. The therapeutic indication of CDK5 inhibitors needs to consider the nature of injury.

The spinal cord dorsal horn (DH) integrates sensory processing but undergoes critical plasticity following nerve injury, leading to mechanical allodynia, or “touch-evoked pain”. It has been proposed that after nerve injury, innocuous sensory neurons gain access to nociceptive-specific (NS) circuits in the DH due to altered spinal inhibitory controls, thereby converting touch into pain. It is however unclear how sensory processing is reorganized under these conditions to generate this symptom. In this study, we used two-photon calcium imaging in mice to show that spinal disinhibition or nerve injury converts most DH excitatory neurons into highly polymodal cells, and unmasks an unprecedented number of previously silent neurons responding to a wide dynamic range (WDR) of sensory modalities. Using computational modeling, we further show that neuropathic pain likely does not result primarily from the transformation of excitatory NS neurons into WDR neurons, but rather from the activation of this previously dormant circuit. Nerve injury alters sensory processing leading to neuropathic pain. In this study, the authors show that loss of spinal inhibition after injury in mice does not seem to let nociceptive neurons be activated by innocuous stimuli, but rather unmasks a previously silent circuit which likely drives pain.

OBJECTIVES:To examine the determinants of acute pain following tooth extraction, within a set of factors belonging to different domains: biometry, dental nosology and anatomy, psychology toward pain and surgery, and surgical procedure. METHODS:Participants were recruited in two centres in France and Lebanon. A 'simple extraction' (161 patients) and a 'wisdom teeth/tooth' group (at least mandibular) (115 patients) were studied separately. Postoperative pain and total analgesic drug intake (over 5 days) were both expressed as a composite score. Both scores were ranked within each surgery group, and their sum was the primary outcome, which was analysed by multivariable linear mixed models after a factor selection. RESULTS:In the simple extraction group, the primary outcome was predicted positively by preoperative fearfulness (defined by a composite of various phobias) and preoperative dental pain, and negatively by age (≥ 60) and a previous tooth extraction. In the wisdom teeth/tooth group, it was predicted positively by preoperative fearfulness and pain catastrophising, and negatively by a local inflammatory context and preoperative dental pain. CONCLUSIONS:Whereas postoperative pain was constantly favoured by psychological distress, age and other dental factors had different influences on postoperative pain depending on the type of extraction. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05405088.

Although recent research suggests that regulatory T (Treg) cells may be involved in migraine pathophysiology, no review has provided a comprehensive assessment of their levels in this condition. This systematic review and meta-analysis aims to assess Treg levels in migraine patients. We systematically searched PubMed, Embase and Cochrane on July 5, 2024 (updated on March 19, 2026), and included all original studies providing data on Treg levels in migraine. Among 1,162 studies identified, five were included in the narrative review and four in the meta-analysis. Data were pooled using a random-effects model. Standardized mean differences (SMD) were calculated to compare peripheral whole blood Treg levels between migraine and control groups. Our narrative review showed decreased Treg levels in three of five studies comparing migraine patients and controls, and in two of three studies on interictal episodic migraine patients and controls. Our meta-analysis of few but carefully selected data suggested a significant decrease in Treg cell levels in migraine (SMD − 4.21 [-7.76; -0.66], p = 0.02, I²=98.3

Parthenolide (PTL) and salicin (SA), the main active components in Feverfew (Tanacetum parthenium) and White Willow (Salix alba), respectively, have been traditionally used as a remedy for various types of pain, including headaches. Because PTL and SA have different mechanisms of action, we hypothesize that a combination of these drugs would result in an additive effect. We investigated the effects of local and/or systemic administration of PTL, SA, or their combination on cephalic mechanical hypersensitivity (MH) in acute and chronic model of migraine induced by dural application of inflammatory soup (IS) in rats of both sexes. We also studied the effect of combination of PTL and SA on the sensitization of the trigeminocervical complex (TCC) induced by IS application using immunohistochemical (calcitonin gene-related peptide [CGRP] expression) and electrophysiological approaches. When combining low doses of PTL (2.5 mg/kg) and SA (5 mg/kg), we found that single systemic administration of combination prevented acute cephalic MH only in females. However, when administered daily, the combination prevented both chronic ictal and interictal cephalic MH as well as the IS-induced increase in CGRP-immunoreactivity within the TCC, in both sexes. Notably, a single dural application of the combination also prevented acute sensitization of TCC wide dynamic range neurons. Combining PTL and SA have an antimigraine effect in both male and female rats. The combination exerts its preventive effect, at least in part, by blocking the afferent inputs from the dura during the induction phase, preventing thus the establishment of central sensitization.

Assessing heart rate variability (HRV) before a standardized surgery would help to explore further the relationship between the autonomic nervous system and pain. A single-center prospective cohort of 117 patients (55

While acute nociceptive pain is a crucial warning system that protects us from injury or disease,chronic pain is not protective,but a pathological condition.As such,it is now recognized as a disease in its own right,which major classes refer to inflammatory,neuropathic,and idiopathic pain.It is frequent,with up to a third of the population that may suffer at one point from chronic pain.It is often associated with other pathologies,including sleep disorders,anxiety,depression,and is still difficult to treat.It thus represents a significant burden in terms of health and societal impact(Tracey et al.,2019).The mechanisms of chronic pain involve multiple diverse pathways in both the peripheral and central nervous systems(CNS),reflecting its multifaceted biology.Indeed,research over the past decades has established that central sensitization(enhancement in the function of neurons and circuits in central nociceptive pathways),in particular within the dorsal horn,the first central relay of nociceptive inputs plays a key role in the chronicity of pain(Latremoliere and Woolf,2009).

In addition to headache, migraine patients often experience sensory hypersensitivity to external stimuli. While photophobia and phonophobia are part of the diagnostic criteria of migraine, many patients also exhibit cutaneous allodynia and osmophobia. However, the presence and intensity of these four hypersensitivities are rarely assessed systematically and simultaneously due to the lack of a simple and rapid self-report questionnaire. We have identified existing questionnaires for allodynia, photophobia and phonophobia and selected one of each, that were translated in French and validated (according to COSMIN’s recommendations). We also proposed a 2-item questionnaire (presence and intensity) for each of these 3 hypersensitivities plus osmophobia, resulting in the 8-item Migraine Hypersensitivity Questionnaire (MHQ-8) exploring these four hypersensitivities. In addition, the headache impact test (HIT-6), the migraine disability assessment (MIDAS) and the hospital anxiety and depression scale (HADS) were also answered. The survey was conducted in Pain and Neurology departments during specialised consultations for headaches. Content validity, structural validity, internal consistency, transcultural validity, reliability, criterion validity, construct validity and responsiveness were tested. Confirmatory factor analysis (CFA) was used to test the dimensionality of the questionnaires. The study sample consisted in N = 329 patients with a mean age of 43.7 ± 13.2 and a mean number of 10.2 ± 7.0 migraine days per month; 84

OBJECTIVE:To determine the prevalence of Burning mouth syndrome (BMS) in patients with Parkinson's disease (PD) and compare it with an age- and sex-matched control group. METHODS:The study included 150 PD patients and 150 age- and sex-matched control subjects. Participants were asked about any possible burning or tingling sensation in the oral mucosa. Those who responded positively underwent a clinical examination and blood analysis to help in diagnosing BMS. RESULTS:Prior to clinical examination, the prevalence of probable BMS was 6.7% (10/150) in PD patients and 2% (3/150) in the control group. After the clinical examination, 6 participants were excluded (3 from each group), resulting in a BMS prevalence of 4.7% in the PD group (7/150) and 0% in the control group (0/150). The difference in prevalence between the two groups was statistically significant (p = 0.015). Patients reported that their BMS symptoms began either after or around the time of their PD diagnosis. CONCLUSIONS:BMS is more prevalent in PD patients than in the general population, indicating a potential role of dopaminergic system dysfunction in BMS pathophysiology. The onset of BMS symptoms after or around the time of PD diagnosis suggests that BMS may be a secondary condition.

Chronic facial pain, a frequent and disabling condition, is maintained by central sensitization, which results in pain hypersensitivity. Although it is well established that reactive astrocytes play a key role in persistent pain mechanisms, the role of disruption of the normal capacity of astrocytes to maintain neuronal homeostasis is much less known. Here we show that persistent facial inflammation disturbs potassium homeostasis in the medullary dorsal horn of male rats, due to a sex-specific, drastic downregulation of astroglial inward rectifier potassium Kir4.1 channels. Using selective genetic tools, we establish that such downregulation, likely due to the release of IL-1β during inflammatory processing, is sufficient and required to drive pain hypersensitivity through altered K+ baseline levels. We further show that this chain of events can be prevented by selective upregulation of astroglial Kir4.1, or through systemic administration of 5-azacytidine, a DNA methylation modulator. Our results thus reveal a critical mechanism by which astrocyte dysfunction drives persistent inflammatory facial pain in males and discover the therapeutic potential of targeting central Kir4.1 for treating this disease.

Neuropathic pain results from peripheral lesion, causing maladaptive plasticity and central sensitization. Clinical and preclinical studies demonstrate that modifications of primary sensory cortex (S1) activity are essential for neuropathic pain persistence. Rodent studies report heightened S1 pyramidal cell excitability in neuropathic pain model, the origins of which remain debated. The axon initial segment, the action potential trigger zone, is a major determinant of neuronal excitability and is known to undergo structural changes after neural perturbation but its role in chronic pain is poorly understood and no studies have explored its role in cortical hyperexcitability in chronic pain models. Besides, despite a higher prevalence of chronic pain in women, most of preclinical studies have been conducted in males. By integrating electrophysiology, immunohistochemistry, and computational modeling, this study demonstrates that in a trigeminal neuropathic pain rat model, sex-specific structural plasticity of the axon initial segment enhances the excitability of layer 5 pyramidal cells in the somatosensory cortex, potentially driving network-level hyperactivity. ### Competing Interest Statement The authors have declared no competing interest. * AIS : axon initial segment AnkG : AnkyrinG CaMKIIα : Calcium/calmodulin-dependent protein kinase type II subunit alpha IONL : infraorbital nerve ligation S1BF : primary cortex barrel field L5PC : layer 5 pyramidal cells FS : Fast-Spiker d.p.s : days post-surgery CAd-LIF : conductance-based adaptative leaky integrate-and-fire Emergence Program Label I-SITE CAP20-25, Homeocode French government IDEX-ISITE initiative, 16-IDEX-0001 Agence Nationale de la Recherche, ANR-24-CE16-1319 ERDF-Project Brain dynamics, CZ-02-0101/00/22_008/0004643

BACKGROUND:Understanding intraoral factors that modulate pain in patients with burning mouth syndrome (BMS) could provide insight into its pathophysiological mechanisms, facilitating improved management strategies. METHODS:This retrospective study included 120 BMS patients who were asked, without predefined options, about factors that alleviated or exacerbated their pain. Data collected included pain characteristics (intensity, localisation, duration) and associated conditions such as salivary abnormalities and taste disturbances. RESULTS:A total of 89.2% of patients reported that intraoral factors influenced their pain, while 10.8% experienced no change with local stimulation. Pain relief was reported by 69.7% of patients, primarily attributed to eating, chewing or sucking (91.6%) and to a lesser extent, consuming cold foods or drinks (20.5%). Pain aggravation was noted in 50.4% of patients, with 91.5% citing intraoral triggers such as acidic, spicy or salty foods, while 11.9% reported worsened pain with hot foods or drinks. No associations were found between pain-modulating factors and age, sex, disease duration, pain intensity or dysgeusia. However, pain relief was more frequent in patients without xerostomia, while those experiencing pain aggravation were more likely to have salivary abnormalities. CONCLUSION:These findings indicate that intraoral factors can modulate pain intensity in the vast majority of BMS patients, supporting the role of the peripheral nervous system in BMS pathophysiology. Understanding these triggers may provide clinicians with valuable insights into the underlying mechanisms of pain, enabling more targeted and effective medical management.

BACKGROUND AND PURPOSE:Preclinical studies in mice highlight delta opioid receptors (DOPs) as a potential migraine treatment. Here, we examined their role in a rat model of migraine in both sexes. EXPERIMENTAL APPROACH:We assessed DOP distribution in the trigeminal ganglion (TG) using RNAscope, the action of the DOP agonist SNC80 on facial mechanical sensitivity using von Frey hairs and responses of trigeminal nucleus caudalis wide dynamic range (WDR) neurons using in vivo electrophysiology, in physiological conditions and a migraine model induced by isosorbide dinitrate (ISDN) injections. KEY RESULTS:In naive rats, DOP mRNA was expressed by large-diameter myelinated NF200-positive TG neurons predominantly and by some CGRP peptidergic neurons, but rarely by IB4-binding nonpeptidergic unmyelinated neurons, with no sex difference. Intravenous SNC80 inhibited WDR neuron responses to noxious mechanical stimuli equally in both sexes. In acute conditions, SNC80 inhibited ISDN-induced MH in a dose-dependent manner equally in both sexes, through peripheral and central DOPs. After chronic administration of ISDN, the distribution of DOP mRNA increased in the TG of females only, specifically in NF200-positive neurons. Subcutaneous SNC80 reversed the interictal and, more in females than in males, the chronic ictal cephalic mechanical hypersensitivity, by acting through peripheral DOPs in females and through central DOPs in males. CONCLUSION AND IMPLICATIONS:DOP-mediated antimigraine effect is stronger in female than male rats and appears to be mediated in chronic conditions through peripheral DOPs in females and central DOPs in males. The results strengthen the relevance of using DOP agonists to treat migraine.

OBJECTIVES/BACKGROUND:Our aim was to compare the temporal dynamics of light and cephalic mechanical sensitivities in male and female mice as they relate to migraine chronicization. Cutaneous and light hypersensitivities are among the most common features of migraine, with greater severity observed in females. In 3% of patients, episodic migraine progresses to a chronic form, and sensory hypersensitivity becomes persistent. The pathophysiology underlying this transformation is complex and not fully understood. Moreover, studies comparing the evolution of sensory hypersensitivity between sexes are scarce. METHODS:Systemic administration of isosorbide dinitrate (ISDN, 10 mg/kg) was used to induce migraine-like behaviors in C57BL/6 mice. Cephalic sensitivity was assessed using periorbital von Frey testing. Light sensitivity was evaluated using the elevated plus maze and light/dark box paradigms. The effectiveness of current migraine treatments, sumatriptan (1 mg/kg) and propranolol (20 mg/kg), was also evaluated. RESULTS:A single ISDN injection induced transient cephalic mechanical hypersensitivity in both males and females, with no sex differences observed. Acute treatment with sumatriptan effectively blocked this hypersensitivity, showing similar efficacy in both sexes. Notably, light hypersensitivity was induced exclusively in acute ISDN-treated females, developing earlier, and persisting longer than cephalic mechanical hypersensitivity. Repeated ISDN administration resulted in persistent and dose-dependent sensory hypersensitivity in both sexes. Interestingly, the chronicization patterns were sex-specific; ISDN-treated females developed persistent light and cephalic mechanical hypersensitivities simultaneously, whereas ISDN-treated males showed delayed light aversion. Prophylactic treatment with propranolol prevented the chronicity of cephalic mechanical hypersensitivity in both sexes, and partially attenuated acute ISDN-induced mechanical and light hypersensitivities. CONCLUSION:The progression from acute to chronic ISDN-induced cephalic mechanical and light hypersensitivities has sex-specific characteristics that mimic the clinical features of migraine. These findings support the involvement of distinct underlying mechanisms and highlight the need for tailored treatment strategies to optimize migraine management in both male and female populations.

Although several meta-analyses have emphasised the role of inflammation in migraine, none has accounted for the diversity of its clinical manifestations. This systematic review and meta-analysis aims to provide a comprehensive and reliable assessment of cytokine levels in migraine. We systematically searched PubMed, Embase and Cochrane up to July 4–5, 2024. Original studies providing data on cytokine levels in migraine were included. Non-inclusion criteria covered studies on hemiplegic migraine, controls with tension-type headache, and unclear cytokine identification. The meta-analysis did not cover studies involving less than 10 participants per group or lacking accessible numeral data. Summary data were extracted from each study and pooled using a random-effects model. Standardized mean differences (SMD) were calculated to compare cytokine levels across all relevant biological samples and comparison groups. Fifty-seven studies were included in the narrative review and/or meta-analysis, covering 2850 migraine patients and 2814 controls. In episodic migraine patients versus controls, blood levels of interleukin-6 (SMD 0·36 [95