FLT3 signaling inhibition abrogates opioid tolerance and hyperalgesia while preserving analgesia.

Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model.

Estrous cycle regulates cephalic mechanical sensitivity and sensitization of the trigemino-cervical complex in a female rat model of chronic migraine.

The higher incidence of migraines in women compared with men has led to the inclusion of female animals in pain research models. However, the critical role of the hormonal cycle is frequently overlooked, despite its clear correlation with migraine occurrences. In this study, we show in a rat model of migraine induced by repeated dural infusions of an inflammatory soup (IS) that a second IS (IS2) injection performed in proestrus/estrus (PE, high estrogen) female rats evokes higher cephalic mechanical hypersensitivities than when performed in metestrus/diestrus (MD, low estrogen) or ovariectomized (OV) rats.

Synthesis of diversely substituted pyridin-2(1)-ones and evaluation of their anti-allodynic effect on cutaneous inflammatory mechanical allodynia.

A series of 3,5-disubtituted pyridin-2(1)-ones was synthesized. As part of a structure-activity relationship study performed in this series, structural modifications were based on 3-(indol-4-yl)-5-(pyridin-4-ylamino)pyridin-2(1)-one B, which exhibited a potent anti-allodynic effect in a rat model of inflammatory pain. In this study, new compounds were assessed for their ability to inhibit cutaneous mechanical allodynia in rats by using the capsaicin pain model.

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.

Objective: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect.

Background: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects.

[Specificities of orofacial neuropathic pain].

Head pain and notably orofacial pain differs from spinal pain on pathophysiological, clinical, therapeutic and prognostic levels. Its high prevalence, important impact on quality of life and significant socio-economical burden justify specific study of such type of pain. Among them, neuropathic orofacial pain resulting from disease or trauma of the trigeminal nervous system is among the most difficult types of pain to diagnose and to treat.

Enhanced pain facilitation rather than impaired pain inhibition in burning mouth syndrome female patients.

Background: Deficient endogenous pain modulation has been implicated in the development and exacerbation of chronic orofacial pain. To date, relatively little is known regarding the function of the endogenous pain modulation in patients with burning mouth syndrome (BMS). This case-control study investigated endogenous pain modulation in women with BMS.

GABA and Glycine Receptor-Mediated Inhibitory Synaptic Transmission onto Adult Rat Lamina II PKCγ-Interneurons: Pharmacological but Not Anatomical Specialization.

Mechanical allodynia (pain to normally innocuous tactile stimuli) is a widespread symptom of inflammatory and neuropathic pain. Spinal or medullary dorsal horn (SDH or MDH) circuits mediating tactile sensation and pain need to interact in order to evoke mechanical allodynia. PKCγ-expressing (PKCγ) interneurons and inhibitory controls within SDH/MDH inner lamina II (II) are pivotal in connecting touch and pain circuits.

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model.

The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioural testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate.

Chronic facial inflammatory pain-induced anxiety is associated with bilateral deactivation of the rostral anterior cingulate cortex.

Patients with chronic pain, especially orofacial pain, often suffer from affective disorders, including anxiety. Previous studies largely focused on the role of the caudal anterior cingulate cortex (cACC) in affective responses to pain, long-term potentiation (LTP) in cACC being thought to mediate the interaction between anxiety and chronic pain. But recent evidence indicates that the rostral ACC (rACC), too, is implicated in processing affective pain.

Postnatal development of inner lamina II interneurons of the rat medullary dorsal horn.

Pain processing in young mammals is immature. Despite the central role of the medullary dorsal horn (MDH) in processing orofacial sensory information, the maturation of the neurons within the MDH has been largely overlooked. Combining in vitro electrophysiological recordings and 3D morphological analysis over the first postnatal month in rats, we investigated the age-dependent development of the neurons within the inner lamina II (IIi) of the MDH.

Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia.

Mechanical allodynia, a painful sensation caused by innocuous touch, is a major chronic pain symptom, which often remains without an effective treatment. There is thus a need for new anti-allodynic treatments based on new drug classes. We recently synthetized new 3,5-disubstituted pyridin-2(1H)-one derivatives.

Characteristics of pain in patients with pituitary adenomas: A cross-sectional study.

Background: This study determines the prevalence and particularities of headache and pain with neuropathic characteristics (NC) in a large French group of patients with pituitary adenoma (PA).

Methods: Analysis of validated self-administered questionnaires, radiological characteristics and treatment strategies of PA was performed.

Results: Of the 221 sent questionnaires, 146 could be used for statistical analysis, 50% of which were completed by women.

Five Predictors Affecting the Prognosis of Patients with Severe Odontogenic Infections.

: Dental cellulitis management is no longer a simple procedure, as more and more patients are needing long-time hospitalization, several surgeries and intensive care follow-up. This prospective study seeks to highlight criteria that can split patients with severe odontogenic infection into two groups: those with simple evolution and those for whom complex management is necessary. : In this observational study, all patients considered with a severe odontogenic infection (which necessitated hospital admission, intravenous antibiotics and general anaesthesia) were enrolled between January 2004 and December 2014 from Clermont-Ferrand University Hospital (France).

Ketamine-Magnesium for Refractory Chronic Cluster Headache: A Case Series.

Objectives: To evaluate the safety and efficacy of ketamine-magnesium combination to reduce attacks in a series of patients with refractory chronic cluster headache (rCCH).

Background: Refractory chronic cluster headache (CCH) is a rare but highly debilitating condition that needs new treatment options. A previous publication reported that a single infusion of ketamine-magnesium combination was effective in 2 patients with rCCH.

High Prevalence of Headaches During Covid-19 Infection: A Retrospective Cohort Study.

Objectives: To document the prevalence of new headaches in patients with Covid-19 infection and the potential association with other neuro-sensorial symptoms (anosmia and ageusia). The persistence of these symptoms 1 month after recovery was also documented.

Background: Headaches are a very common symptom of viral infections.

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia.

The dorsal horns of the spinal cord and the trigeminal nuclei in the brainstem contain neuron populations that are critical to process sensory information. Neurons in these areas are highly heterogeneous in their morphology, molecular phenotype and intrinsic properties, making it difficult to identify functionally distinct cell populations, and to determine how these are engaged in pathophysiological conditions. There is a growing consensus concerning the classification of neuron populations, based on transcriptomic and transductomic analyses of the dorsal horn.

PKCγ interneurons, a gateway to pathological pain in the dorsal horn.

Chronic pain is a frequent and disabling condition that is significantly maintained by central sensitization, which results in pathological amplification of responses to noxious and innocuous stimuli. As such, mechanical allodynia, or pain in response to a tactile stimulus that does not normally provoke pain, is a cardinal feature of chronic pain. Recent evidence suggests that the dorsal horn excitatory interneurons that express the γ isoform of protein kinase C (PKCγ) play a critical role in the mechanism of mechanical allodynia during chronic pain.

Pyridin-2(1H)one derivatives: A possible new class of therapeutics for mechanical allodynia.

Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA.

Whole-body reversible neuropathic pain associated with right parieto-temporal operculum single inflammatory lesion in a patient with multiple sclerosis: A case report.

Background: The posterior insula and the medial parietal operculum (PIMO) are part of the pain network. Pain can be induced by direct stimulation of the PIMO, but the clinical consequence of lesions in this brain area is not well known.

Case Report: We report the case of a patient with multiple sclerosis who presented a relapse characterized by isolated widespread neuropathic pain.

Increased cerebral responses to salient transitions between alternating stimuli in chronic migraine with medication overuse headache and during migraine attacks.

Introduction: In a previous study exploring central pain modulation with heterotopic stimuli in healthy volunteers, we found that transitions between sustained noxious and innocuous thermal stimulations on the foot activated the "salience matrix". Knowing that central sensory processing is abnormal in migraine, we searched in the present study for possible abnormalities of these salient transitional responses in different forms of migraine and at different time points of the migraine cycle.

Methods: Participants of both sexes, mostly females, took part in a conditioned pain modulation experiment: Migraineurs between (n = 14) and during attacks (n = 5), chronic migraine patients with medication overuse headache (n = 7) and healthy volunteers (n = 24).

5-HT Receptor-Induced Morphological Reorganization of PKCγ-Expressing Interneurons Gates Inflammatory Mechanical Allodynia in Rat.

Mechanical allodynia, a widespread pain symptom that still lacks effective therapy, is associated with the activation of a dorsally directed polysynaptic circuit within the spinal dorsal horn (SDH) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (II) interneurons expressing the γ isoform of protein kinase C (PKCγ) are key elements for allodynia circuits, but how they operate is still unclear. Combining behavioral, electrophysiological, and morphological approaches in an adult rat model of facial inflammatory pain (complete Freund's adjuvant, CFA), we show that the mechanical allodynia observed 1 h after CFA injection is associated with the following (1) sensitization (using ERK1/2 phosphorylation as a marker) and (2) reduced dendritic arborizations and enhanced spine density in exclusively PKCγ interneurons, but (3) depolarized resting membrane potential (RMP) in all lamina II PKCγ/PKCγ interneurons.

Dural and pial pain-sensitive structures in humans: new inputs from awake craniotomies.

Our knowledge on intracranial pain-sensitive structures in humans comes essentially from observations during neurosurgical procedures performed in awake patients. It is currently accepted that intracranial pain-sensitive structures are limited to the dura mater and its feeding vessels and that small cerebral vessels and pia mater are insensitive to pain, which is inconsistent with some neurosurgical observations during awake craniotomy procedures. We prospectively collected observations of painful events evoked by mechanical stimulation (touching, stretching, pressure, or aspiration) of intracranial structures during awake craniotomies, routinely performed for intraoperative functional mapping to tailor brain tumour resection in the eloquent area.