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International audience; Background: Early life stress is known to affect the development of the nervous system and its function at a later age. It increases the risk to develop psychiatric disorders as well as chronic pain and its associated affective comorbidities across the lifespan. GABAergic inhibition is important for the regulation of central function and related behaviors, including nociception, anxiety or social interactions, and requires low intracellular chloride levels. Of particular interest, the oxytocinergic (OTergic) system exerts potent anxiolytic, analgesic and pro-social properties and is known to be involved in the regulation of chloride homeostasis and to be impaired following early life stress.Methods: We used behavioral measures to evaluate anxiety, social interactions and pain responses in a rat model of neonatal maternal separation (NMS). Using quantitative PCR, we investigated whether NMS was associated with alterations in the expression of chloride transporters in the cerebrum and spinal cord. Finally, we evaluated the contribution of OTergic signaling and neuro-inflammatory processes in the observed phenotype.Results: NMS animals displayed a long-lasting upregulation of chloride importer Na-K-Cl cotransporter type 1 (NKCC1) expression in the cerebrum and spinal cord. Neonatal administration of the NKCC1 inhibitor bumetanide or oxytocin successfully normalized the anxiety-like symptoms and the lack of social preference observed in NMS animals. Phenotypic alterations were associated with a pro-inflammatory state which could contribute to NKCC1 upregulation.Conclusions: This work suggests that an impaired chloride homeostasis, linked to oxytocin signaling dysfunction and to neuro-inflammatory processes, could contribute to the sensori-affective phenotype following NMS.

Inflammatory processes are critical promoting factors of chronic pain states, mostly by inducing peripheral and central sensitization of the nociceptive system. These processes are associated with a massive increase in glutamatergic transmission, sometimes facilitated by spinal disinhibition. In this study, we used etifoxine, a non-benzodiazepine anxiolytic known to amplify inhibition mediated by gamma-aminobutyric acid type A (GABAA) receptors in pain processing regions, either directly (through allosteric modulation) or indirectly (through the synthesis of endogenous neurosteroids). We used different models of local inflammation to evaluate the possible direct action of etifoxine on analgesia and edema. Pain symptom and edema measurements were performed after intraplantar carrageenan injection or after topical ear inflammation. We found that etifoxine treatment was associated with reduced plantar surface temperature 24 h after intraplantar carrageenan injection. In this model, etifoxine also alleviated thermal hot and mechanical hyperalgesia. A similar finding was observed while analyzing pain symptoms in the late phase of the formalin test. In a model of ear inflammation, etifoxine appeared to have a moderate anti-edemic effect after topical application. This slight action of etifoxine on the limitation of inflammatory processes could be mediated in part by cyclo-oxygenase 1 activity inhibition. Etifoxine appears as a promising therapeutic tool contributing to the limitation of inflammatory pain symptoms. Since etifoxine is already prescribed as an anxiolytic in several countries, it could be a good candidate for the prevention of inflammatory-driven edema and hyperalgesia, although the precise mechanism of action relative to its anti-inflammatory potential remains to be elucidated.

International audience; Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

Resume Pendant de nombreuses annees, le monde medical n’a pas reconnu la capacite du jeune enfant a ressentir la douleur. Parmi les arguments avances, la question de l’immaturite du systeme nociceptif et de la myelinisation des circuits nociceptifs ont ete des arguments majeurs utilises pour expliquer l’absence de souvenirs douloureux dans les premieres annees de vie. Les travaux d’Anand et al., publies a la fin des annees 1980, ont permis de corriger ce prejudice. Il est maintenant clairement etabli que l’organisation neuroanatomique du systeme nociceptif est fonctionnelle au debut du troisieme trimestre de la vie fœtale permettant d’observer une integration corticale des messages nociceptifs peripheriques. L’immaturite du systeme nociceptif, evoquee en fin de grossesse et au debut de la vie extra-uterine, touche plus specifiquement les filtres inhibiteurs au sein du systeme nerveux central dont ceux de la moelle epiniere. De nombreux progres doivent encore etre realises dans la prise en charge de la douleur chez l’enfant. Plus de 20 ans apres la publication des travaux d’Anand, il etait constate que seulement 20 a 30 % des interventions douloureuses etait effectuees a l’aide d’une analgesie preemptive chez les enfants nouveau-nes prematures, par exemple. Dans cette revue, le developpement du systeme nociceptif du nouveau-ne et son expression douloureuse seront tout d’abord presentes. Evaluer la douleur chez le nouveau-ne reste effectivement un challenge puisqu’il lui est impossible de l’exprimer sous forme d’une plainte intelligible. Des approches indirectes, basees sur l’observation de « signes » de douleur sont donc necessaires et ont ete developpees. Il s’agit par exemple de l’evaluation des reponses autonomes a la douleur : frequence cardiaque, frequence respiratoire, pression arterielle ou mesure de la saturation en oxygene du sang. Ces donnees peuvent etre associees utilement a la mesure d’indicateurs comportementaux bases sur l’observation generale des mouvements du corps, de l’etat d’agitation de l’enfant, de la duree des pleurs ou encore de l’analyse de l’expression faciale (froncement des sourcils, ouvertures des levres, contraction des paupieres…). Au-dela de la question de la reconnaissance de la douleur chez l’enfant, les consequences a long terme de la prise en charge des nouveau-nes dans les unites de soins intensifs sont un sujet d’inquietude. Ces perturbations perinatales douloureuses et non-douloureuses (c.-a-d. exces de stimulations sensorielles, deficit d’interaction mere–enfant…) semblent laisser une empreinte a long terme au sein meme du systeme nociceptif. L’enfant devenu adulte montre ainsi une reponse accentuee ou inappropriee vis-a-vis des stimulations douloureuses, un risque plus eleve de developper des douleurs chroniques et plus generalement, fait preuve d’une mauvaise adaptation vis-a-vis des stress environnementaux. Les alterations a long terme de la reponse douloureuse, induites par les procedures douloureuses neonatales ou par la mauvaise qualite des interactions mere–enfant, seront presentees a la fin de cette revue. Les donnees recentes de la recherche fondamentales sur des modeles animaux et sur les mecanismes associes seront egalement evoquees.

Resume Les cornes dorsales de la moelle epiniere constituent le premier relais pour les messages nociceptifs avant leur transmission vers les structures supraspinales dont fait partie le cortex, siege de l’elaboration de la sensation douloureuse. Au niveau de ce premier relais medullaire, l’integration des messages nociceptifs par les neurones de la corne dorsale est determinee par un equilibre fragile entre les controles excitateurs et inhibiteurs. Beaucoup de travaux de recherches ont montre que les controles excitateurs sont exacerbes lors du developpement des douleurs inflammatoires et neuropathiques. La contribution des controles inhibiteurs qui president a l’apparition des symptomes douloureux etait jusqu’a present meconnue. Dans cette revue sont presentes plusieurs exemples recents qui montrent comment la production de certains mediateurs de l’inflammation ou l’alteration de l’homeostasie des ions chlorure aggrave l’hypersensibilite douloureuse en produisant une desinhibition spinale des circuits glycinergiques et GABAergiques. Certaines tentatives de compensation semblent neanmoins limiter cette desinhibition et nous venons d’identifier le role de neurosteroides dans un modele de sensibilisation douloureuse inflammatoire. L’identification de ces mecanismes devrait permettre de developper a terme de nouvelles strategies therapeutiques visant a accentuer les controles inhibiteurs medullaires.

As a first step towards elucidating mechanisms involved in neuroendocrine synaptogenesis, we developed a model of co-culture based on hypothalamic-intermediate pituitary interactions. Dissociated hypothalamic neurons from fetal rats at embryonic day 15 were cultured in a defined medium together with melanotrope cells of the pituitary intermediate lobe from neonatal rats. In these co-cultures, establishment of synaptic contacts between GABAergic or dopaminergic neurons and an endocrine target cell, the melanotrope cell, was studied by morphofunctional approaches. Using double immunostaining with antibodies directed against glutamate decarboxylase or tyrosine hydroxylase and AE-melanocyte-stimulating hormone, we demonstrated morphological contacts between GABAergic or dopaminergic neurons and melanotrope cells as early as three days in vitro. Furthermore, using an antibody directed against synapsin I, we showed a modification of synapsin I immunoreactivity from diVuse to punctate distribution correlated with the establishment of contacts and the observation of characteristic neuroendocrine synapses by electron microscopy. These results were further confirmed by electrophysiological studies. Patch-clamp recordings demonstrated that, at six days in vitro, some melanotrope cells displayed GABAergic synaptic currents, which occurred either spontaneously and/or could be evoked chemically by 50 mM KCl or 100 µM kainate. The proportion of the melanotrope cells receiving functional synaptic inputs increased until 10 days in culture, a stage at which virtually all melanotrope cells in contact with neurons possessed functional synapses. The results presented here describe the establishment of neuroendocrine synapses in vitro, studied by combining morphofunctional and electrophysiological approaches. Copyright ? 1996 IBRO. Published by Elsevier Science Ltd.