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Two cases of pain evoked by cold food ingestion, following root canal therapy (RCT), are presented. The source of pain was detected when cold application to the vestibular, periapical area corresponding to the teeth involved evoked strong pain of about 30 sec durations. In the first case, the patient suffered from strong pain in the right mandibular area over the last 4 months. After successive RCT of 3 right mandibular teeth the spontaneous pain eased significantly, but strong pain evoked by cold food ingestion persisted. Cold application to the vestibular periapical area of teeth involved identified the source of pain, which was abolished by 80 mg/day of slow-release propranolol. In the second case, cold allodynia developed after RCT. The RCT was performed for prosthetic reasons with no prior pain. Pain could be duplicated by cold application to the vestibular area of the treated tooth. The patient preferred no treatment when the source of pain was explained. In both cases cold application did not produce any pain in other intra oral locations, including the contralateral vestibular area or the mid soft or hard palate. Pain mechanisms, neurovascular and neuropathic, which differ for each case are discussed.

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BACKGROUND: Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. RESULTS: DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-𝛼 expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. CONCLUSIONS: DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.

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Neonatal exposure to noxious stimuli such as repeated heel lances can cause behavior changes. In the NICU sucrose given prior to procedures attenuates the immediate behavioral response to noxious stimuli but may not ameliorate the long-term consequences, and treatment with 24% sucrose can brain structure and behavior in adult rodents. We used a rat model to determine whether paw pricks during the neonatal period alter social interaction and/or paw withdrawal thresholds (PWT) in adolescence, and if 7% sucrose mitigates these effects. One male and one female pup per litter was assigned to each of six experimental groups (no paw prick (control), 1 paw prick (1PP), or 2PP, ± sucrose). Hind paws were pricked once or twice each day between postnatal day (P)3 and P10. Social behavior and PWT were tested in adolescence using the modified social interaction test and von Frey filaments, respectively. Social behavior was altered in the 2PP group; total time interacting was lower in 2PP rats, primarily due to less time sniffing a play partner. Sucrose did not mitigate effects of paw prick but trended to alter social behaviors in males; it decreased time in contact but increased social motivation (movement toward a play partner). PWTs were higher in 2PP animals, this was not altered by sucrose. Thus, rat pups exposed to paw pricks in the neonatal period have some altered behaviors in adolescence. The nature of the behavioral changes is sex-dependent, but sucrose did not mitigate these changes.

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BACKGROUND: Migraine is one of the most common primary headaches worldwide, while toothache is the most common pain in the orofacial region. The association of migraine pain, and oral pain is unknown. This study aims to investigate the association between migraine and dental and gingival pain with the presence of allodynia. METHODS: A questionnaire comprising demographic data with the ID-Migraine (IDM) tool, an Allodynia Symptom Checklist (ASC), and inquiries about pain and sensitivity in the teeth and gums during migraine attacks was administered to the participants and 762 responded the survey. The study classified participants based on the ASC, and the relationship between allodynia and pain/sensitivity in the teeth and/or gums during migraine attacks was analyzed. The statistical analyses utilized Chi-square tests and the Fisher-Exact test. RESULTS: Among 762 migraine patients, 430 (56.44%) were classified as allodynia (+), while 332 (43.56%) were classified as allodynia (-) (p < 0.001). Additionally, 285 participants (37.5%) reported experiencing pain and sensitivity in the teeth and gums during migraine attacks, with a significant relationship observed between allodynia and pain/sensitivity in the teeth and/or gums during migraine attacks (p < 0.001). CONCLUSION: The findings of this study have important clinical implications. For migraine patients who are non-allodynic, the presence of pain and sensitivity in their teeth and gums during migraine attacks may indicate underlying dental diseases or the need for dental treatment especially root canal treatment. However, for allodynic patients, such symptoms may not necessarily indicate the presence of dental diseases or the need for dental treatment especially root canal treatment. These results underscore the significance of considering the presence of allodynia in the assessment and management of oral symptoms during migraine attacks.

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Chronic orofacial pain disorders are common debilitating conditions, affecting the trigeminal system. Its underlying pathophysiological mechanisms are still unclear and the therapy is often unsatisfactory, therefore, preclinical models are crucial to identify the key mediators and novel treatment options. Complete Freund's adjuvant (CFA)-induced orofacial inflammatory allodynia/hyperalgesia is commonly used in rodents, but it has not been validated with currently used drugs. Here we tested the effects of the adjuvant analgesic/antiepileptic voltage-gated Na+ channel blocker complex mechanism of action topiramate in comparison with the gold standard antimigraine serotonin 5-HT1B/D receptor agonist sumatriptan in this model. CFA was injected subcutaneously into the right whisker pad of male Sprague-Dawley rats (250-300 g), then mechanonociceptive threshold values were investigated with von Frey filaments (3, 5, and 7 days after CFA injection). Effects of topiramate (30 mg/kg per os) and sumatriptan (1 mg/kg subcutaneous) on the adjuvant-induced chronic inflammatory orofacial allodynia were investigated 60, 120, and 180 min after the treatments each day. To determine the optimal concentration for drug effect analysis, we tested the effects of two different CFA-concentrations (1 and 0.5 mg/mL) on mechanonociceptive thresholds. Both concentrations of CFA induced a chronic orofacial allodynia in 60% of all rats. Although, higher CFA concentration induced greater allodynia, much more stable threshold reduction was observed with the lower CFA concentration: on day 3 the thresholds decreased from 18.30 g to approximately 11 g (low) and 5 g (high), respectively, however a slight increase was observed in the case of higher CFA concentration (on days 5, 7, and 11). In all investigation days, topiramate showed significant anti-allodynic effect comparing the pre and post drug dose and comparing the vehicle treated to the drug treated groups. Sumatriptan also caused a significant threshold increase compared to pre dose thresholds (day 3) and also showed a slight anti-allodynic effect compared to the vehicle-treated group (day 3 and 5). In the present study CFA-induced chronic orofacial allodynia was reversed by topiramate in rats validating the model with the adjuvant analgesic. Other than establishing a validated orofacial pain-related syndrome model in rats, new ways are opened for the repurposing of topiramate.

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Carpal tunnel syndrome (CTS) is the most frequent entrapment neuropathy. Patients commonly experience neuropathic pain, leading them to seek medical advice. However, other symptoms experienced in patients with CTS, such as paresthesia, dysesthesia and allodynia, classed as positive sensory symptoms (PSS), are often under-reported. In the present study, patients with surgically-managed CTS were observed pre- and post-surgery to evaluate PSS, using the symptoms scale component of the Boston Carpal Tunnel Questionnaire (BCTQ) and the Sensory Frequency of Symptoms Scale. In total, 19 patients were included in the present study, with 79% female patients, and a mean age of 54±10.59 years. In addition, the mean follow-up was 63±29.91 months. The results of the present study revealed a pre-surgery BCTQ score of 3.52±0.63 and a post-surgery BCTQ score of 1.58±0.61. Notably, improvements in pain were observed, at 7.7±2.26 pre-surgery compared with 1.65±2.88 post-surgery. Compared with pre-surgery, post-surgery paresthesia scores were reduced from 2.94±0.82 to 0.47±0.45, dysesthesia scores were reduced from 2.52±0.84 to 0.47±0.39 and allodynia scores were reduced from 0.63±0.75 to 0.26±0.47. In conclusion, the results of the present study demonstrated that median nerve decompression ameliorated CTS symptoms, such as paresthesia and dysesthesia. However, further investigations are required to verify the benefits of surgery in relieving allodynia.

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BACKGROUND: OnabotulinumtoxinA (onabotA), is assumed to achieve its therapeutic effect in migraine through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with central dura-sensitive trigeminovascular neurons in the spinal trigeminal nucleus (SPV). The present study investigated the mechanism of action of onabotA by assessing its effect on activation and sensitization of dura-sensitive neurons in the SPV by cortical spreading depression (CSD). It is a follow up to our recent study on onabotA effects on activation and sensitization of peripheral trigeminovascular neurons. METHODS: In anesthetized male and female rats, single-unit recordings were used to assess effects of extracranial injections of onabotA (five injections, one unit each, diluted in 5 µl of saline were made along the lambdoid (two injection sites) and sagittal (two injection sites) suture) vs. vehicle on CSD-induced activation and sensitization of high-threshold (HT) and wide-dynamic range (WDR) dura-sensitive neurons in the SPV. RESULTS: Single cell analysis of onabotA pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the SPV revealed the ability of this neurotoxin to prevent activation and sensitization of WDR neurons (13/20 (65%) vs. 4/16 (25%) activated neurons in the control vs. treated groups, p = 0.022, Fisher's exact). By contrast, onabotA pretreatment effects on CSD-induced activation and sensitization of HT neurons had no effect on their activation (12/18 (67%) vs. 4/7 (36%) activated neurons in the control vs. treated groups, p = 0.14, Fisher's exact). Regarding sensitization, we found that onabotA pretreatment prevented the enhanced responses to mechanical stimulation of the skin (i.e. responses reflecting central sensitization) in both WDR and HT neurons. In control but not treated WDR neurons, responses to brush (p = 0.004 vs. p = 0.007), pressure (p = 0.002 vs. p = 0.79) and pinch (p = 0.007 vs. 0.79) increased significantly two hours after CSD. Similarly, in control but not treated HT neurons, responses to brush (p = 0.002 vs. p = 0.79), pressure (p = 0.002 vs. p = 0.72) and pinch (p = 0.0006 vs. p = 0.28) increased significantly two hours after CSD. Unexpectedly, onabotA pretreatment prevented the enhanced responses of both WDR and HT neurons to mechanical stimulation of the dura (commonly reflecting peripheral sensitization). In control vs. treated WDR and HT neurons, responses to dural stimulation were enhanced in 70 vs. 25% (p = 0.017) and 78 vs. 27% (p = 0.017), respectively. CONCLUSIONS: The ability of onabotA to prevent activation and sensitization of WDR neurons is attributed to its preferential inhibitory effects on unmyelinated C-fibers. The inability of onabotA to prevent activation of HT neurons is attributed to its less extensive inhibitory effects on the thinly myelinated Aδ-fibers. These findings provide further pre-clinical evidence about differences and potentially complementary mechanisms of action of onabotA and calcitonin gene-related peptide-signaling neutralizing drugs.

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Objectives: The present study investigated the prevalence of mechanical allodynia (MA) in healthy teeth adjacent and contralateral to endodontically diseased teeth. Materials and Methods: This cross-sectional study included 114 patients with symptomatic irreversible pulpitis and apical periodontitis in permanent mandibular first molars who possessed healthy teeth adjacent and contralateral to the endodontically diseased tooth. The mechanical sensitivity of the teeth was determined by percussion testing. The presence or absence of pain on percussion in the teeth adjacent and contralateral to the endodontically diseased tooth and the tooth distal to the contralateral symmetrical tooth was recorded according to coding criteria. The prevalence of MA was computed as a percentage, and binary logistic regression analysis was done. The Fisher exact test and Mann-Whitney U test were used for binary and ordinal data. Results: Age and sex did not influence the prevalence of MA. An increased prevalence of MA was found in patients with higher levels of spontaneous pain (p < 0.001). The prevalence of allodynia was 57% in teeth adjacent to endodontically diseased teeth and 10.5% in teeth contralateral to endodontically diseased teeth. In addition, on the ipsilateral side, there were more painful sensations distal to the diseased tooth than mesially. Conclusions: Despite being disease-free, teeth adjacent and contralateral to endodontically diseased teeth exhibited pain on percussion. There was a direct association between the severity of the patient's pain and the presence of MA.

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Chronobiological approaches have emerged as tools to study pain and inflammation. Although time-of-day effects on the expression of pain after injury have been studied, it remains unaddressed whether the timing of the injury itself can alter subsequent pain behaviors. The aim of this study was to assess postsurgical pain behaviors in a mouse hind paw incision assay in a circadian-dependent manner. Incisions were made at one of four equally spaced time points over a 24-hour period, with evoked and spontaneous pain behaviors measured using the von Frey mechanical sensitivity test, Hargreaves' radiant heat paw-withdrawal test, and the Mouse Grimace Scale. Algesiometric testing was performed in C57BL/6 mice prior to and at multiple time points after incision injury, at the same time of day, until pain resolution. No statistically significant differences were observed between groups. This study adds to the literature on circadian rhythms and their influence on pain in the pursuit of more biologically informed pre- and postoperative care.

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Introduction: We explored in mice, the analgesic, tolerance, dependency, and rewarding effects of systemic acetaminophen (APAP). Methods: Studies employed adult mice (C57Bl6). (1) Intraplantar formalin flinching + post formalin allodynia. Mice were given intraperitoneal APAP in a DMSO (5%)/Tween 80 (5%) or a water-based formulation before formalin flinching on day 1 and tactile thresholds assessed before and after APAP at day 12. (2) Paw incision. At 24 hours and 8 days after hind paw incision in male mice, effects of intraperitoneal APAP on tactile allodynia were assessed. (3) Repeated delivery. Mice received daily (4 days) analgesic doses of APAP or vehicle and tested upon formalin flinching on day 5. (4) Conditioned place preference. For 3 consecutive days, vehicle was given in the morning in either of 2 chambers and in each afternoon, an analgesic dose of morphine or APAP in the other chamber. On days 5 and 10, animals were allowed to select a "preferred" chamber. Results: Formalin in male mice resulted in biphasic flinching and an enduring postformalin tactile allodynia. Acetaminophen dose dependently decreased phase 2 flinching, and reversed allodynia was observed postflinching. At a comparable APAP dose, female mice showed similarly reduced phase 2 flinching. Incision allodynia was transiently reversed by APAP. Repeated APAP delivery showed no loss of effect after sequential injections or signs of withdrawal. Morphine, but not APAP or vehicle, resulted in robust place preference. Conclusions: APAP decreased flinching and allodynia observed following formalin and paw incision and an absence of tolerance, dependence, or rewarding properties.

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Introduction: Millions of people undergo surgical procedures each year with many developing postsurgical pain. Dynamic allodynia can arise when, for example, clothing brushing close to the surgical site elicits pain. The allodynia circuits that enable crosstalk between afferent tactile inputs and central pain circuits have been studied, but the peripheral tactile drive has not been explored. Objective: Investigate the innervation of the skin in the rat plantar hindpaw skin-muscle incision model. Results: Incision increased epidermal thickness and cell layers and reduced intraepidermal nerve fibre density, identified with PGP9.5 immunostaining. Strikingly, Collagen IV immunostaining revealed the development of dermal protrusions, oriented towards the incision site, that were reminiscent of the dermal papillae that exist in glabrous footpads. S100 immunostaining for lamellar Schwann cells revealed the presence of novel tactile corpuscles (S100-positive bulb) within incision-induced putative dermal papillae. The occurrence of these novel tactile corpuscles coincided with behavioural observations of dynamic allodynia. Tactile corpuscles require brain-derived neurotrophic factor- tropomyosin receptor kinase B (BDNF-TrkB) signalling to form during development, and an increase in BDNF-immunostaining intensity was observed close to the incision site. Local acute administration of TrkB-Fc, to block BDNF-TrkB signalling, reduced, by approximately 50%, both tactile corpuscle size (S100+ bulb area) and dynamic allodynia. Conclusion: Surgery induces the development of novel tactile corpuscles in the incision surround, in a BDNF-TrKB-dependent manner, that contributes to postsurgical tactile-evoked pain.

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Pathological nociception arising from peripheral nerve injury impacts quality of life. Current therapeutics are generally ineffective. However, photobiomodulation therapy (PBMT) has shown promise in addressing this issue. We aimed to assess the potential anti-allodynic effects of 2 p.m. protocols, each applied transcutaneously over the peripheral nerve injury. In addition to evaluating nociceptive behavior, we also conducted morphological analysis using electron microscopy (EM) to investigate potential ultrastructural changes at the cellular level. We sought to determine, using the chronic constriction injury (CCI) model, whether our parameters could alleviate established allodynia and/or dampen allodynia development. Adult male and female rats with CCI or sham were treated with PBMT (850-nm wavelength) for 2 min, 3 times a week over three or four weeks across three studies, where PBMT began either before or after CCI. Allodynia was assessed prior to surgery and across weeks and, at the conclusion of the third study, sciatic nerve was processed for EM and histomorphometrically evaluated. The results showed that PBMT before versus after CCI injury yielded similar behaviors, effectively decreasing allodynia. Interestingly, these positive effects of PBMT do not appear to be accounted by protection of the sciatic injury site, based on EM. CCI reliably decreased axon size and the number of myelinated axons present in both PBMT and control groups. While PBMT reduced the number of C-fibers in CCI samples, no improvement in any measure was observed in response to PBMT.

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Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.

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Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.

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The parabrachial nucleus (PBN) in the dorsal pons responds to bodily threats and transmits alarm signals to the forebrain. Parabrachial neuron activity is enhanced during chronic pain, and inactivation of PBN neurons in mice prevents the establishment of neuropathic, chronic pain symptoms. Chemogenetic or optogenetic activation of all glutamatergic neurons in the PBN, or just the subpopulation that expresses the Calca gene, is sufficient to establish pain phenotypes, including long-lasting tactile allodynia, that scale with the extent of stimulation, thereby promoting nociplastic pain, defined as diffuse pain without tissue inflammation or nerve injury. This review focuses on the role(s) of molecularly defined PBN neurons and the downstream nodes in the brain that contribute to establishing nociplastic pain.

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Central post-stroke pain (CPSP) is a chronic pain resulting from a lesion in somatosensory pathways. Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) that target the primary motor cortex (M1), have shown promise for the treatment of CPSP. High-frequency (Hf) rTMS exhibits analgesic effects compared to low-frequency (Lf) rTMS; however, its analgesic mechanism is unknown. We aimed to elucidate the mechanism of rTMS-induced analgesia by evaluating alterations of tactile functional magnetic resonance imaging (fMRI) due to Hf- and Lf-rTMS in a CPSP monkey model. Consistent with the patient findings, the monkeys showed an increase in pain threshold after Hf-rTMS, which indicated an analgesic effect. However, no change after Lf-rTMS was observed. Compared to Lf-rTMS, Hf-rTMS produced enhanced tactile-evoked fMRI signals not only in M1 but also in somatosensory processing regions, such as the primary somatosensory and midcingulate cortices. However, the secondary somatosensory cortex (S2) was less active after Hf-rTMS than after Lf-rTMS, suggesting that activation of this region was involved in CPSP. Previous studies showed pharmacological inhibition of S2 reduces CPSP-related behaviors, and the present results emphasize the involvement of an S2 inhibitory system in rTMS-induced analgesia. Verification using the monkey model is important to elucidate the inhibition system.

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Background: Migraine is the fourth most common cause of disability in women and the eighth most common cause in men. Central sensitization phenomena predispose to chronic migraine and are generally more pronounced in women. Objective: The aim of this retrospective observational study was to look for sex differences in a population of migraine subjects attending a tertiary headache center, focusing on symptoms of central sensitization such as allodynia and pericranial tenderness. Methods: This study is based on data collected at a tertiary headache center between January 1, 2018, and December 31, 2022. The clinical interview included the main features of migraine, allodynia, a disability questionnaire, the pericranial tenderness score, and anxiety and depression scales. Results: We selected a total of 1,087 migraine subjects (233 men). Osmophobia predominated in women, as did nausea. Disability scores, headache intensity, allodynia, anxiety, and depression predominated in women, without menopausal age playing a role. The frequency of symptomatic medication use was similar in both sexes. Allodynia score was the largest discriminating factor between women and men. Conclusions: Women with migraine are more likely than men to report acute allodynia, nausea, and osmophobia and are also more likely to be anxious, depressed, and disabled. These features appear to be independent of fertile age and are probably related to sex-specific genetic characteristics. These symptoms represent a tendency toward sensory hypersensitivity and central sensitization that should be carefully assessed in both women and men with migraine with a view to possibly predicting chronic development.

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Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca2+ imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca2+ signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca2+ signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2PVH neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2PVH neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.

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INTRODUCTION: Following amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. METHODS: Twenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. RESULTS: Male and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. CONCLUSION: This novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

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The information provided from the papers reviewed here about the role of epigenetics in chronic craniofacial neuropathic pain is critically important because epigenetic dysregulation during the development and maintenance of chronic neuropathic pain is not yet well characterized, particularly for craniofacial pain. We have noted that gene expression changes reported vary depending on the nerve injury model and the reported sample collection time point. At a truly chronic timepoint of 10 weeks in our model of chronic neuropathic pain, functional groupings of genes examined include those potentially contributing to anti-inflammation, nerve repair/regeneration, and nociception. Genes altered after treatment with the epigenetic modulator LMK235 are discussed. All of these differentials are key in working toward the development of diagnosis-targeted therapeutics and likely for the timing of when the treatment is provided. The emphasis on the relevance of time post-injury is reiterated here.

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