Mas-related G-protein–coupled receptors inhibit pathological pain in mice

An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein–coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8–22 (BAM 8–22), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8–22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn

Background: Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. Results: We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin. Conclusions: These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia

Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target

Glycine Inhibitory Dysfunction Turns Touch into Pain through PKCgamma Interneurons

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCγ). Selective inhibition of PKCγ as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCγ-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCγ might provide a new tool for alleviating allodynia in the clinical setting

GABA Expression and Regulation by Sensory Experience in the Developing Visual System

The developing retinotectal system of the Xenopus laevis tadpole is a model of choice for studying visual experience-dependent circuit maturation in the intact animal. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to play a critical role in the formation of sensory circuits in this preparation, however a comprehensive neuroanatomical study of GABAergic cell distribution in the developing tadpole has not been conducted. We report a detailed description of the spatial expression of GABA immunoreactivity in the Xenopus laevis tadpole brain at two key developmental stages: stage 40/42 around the onset of retinotectal innervation and stage 47 when the retinotectal circuit supports visually-guided behavior. During this period, GABAergic neurons within specific brain structures appeared to redistribute from clusters of neuronal somata to a sparser, more uniform distribution. Furthermore, we found that GABA levels were regulated by recent sensory experience. Both ELISA measurements of GABA concentration and quantitative analysis of GABA immunoreactivity in tissue sections from the optic tectum show that GABA increased in response to a 4 hr period of enhanced visual stimulation in stage 47 tadpoles. These observations reveal a remarkable degree of adaptability of GABAergic neurons in the developing brain, consistent with their key contributions to circuit development and function

Michel Leiris et les revues modernistes : surréalisme, ethnographie et politique

Michel Leiris est né à Paris en 1901. Il fréquente à partir des années 20 des artistes de l’avant-garde française et vient à la littérature par la grâce d’un poète, Max Jacob, et d’un peintre, André Masson. Il admire donc la peinture et certains peintres dont Pablo Picasso, sur lequel il écrira de nombreux articles. Outre l’admiration pour leurs œuvres respectives, une amitié sincère unit le peintre à Michel Leiris, et ce, jusqu’à sa mort. Picasso, retiré dans le sud de la France à la fin de ..

Réunion annuelle du consortium des éditeurs d’OpenEdition Books – 3 avril 2018

Le consortium des éditeurs d’OpenEdition rassemble les éditeurs impliqués dans le développement de la plateforme de publications électroniques OpenEdition Books. En 2018, un peu plus d’une centaine de structures éditoriales sont engagées dans cette initiative. Cette année, l’équipe d'OpenEdition accueille les éditeurs  à la Délégation Paris Michel-Ange du CNRS (3 rue Michel-Ange – 75016 Paris), amphithéâtre Marie-Curie de 14h à 17h30. Le programme – Bilan et perspectives pour l’unité et les p..

Why are some traits of personality more valued from others? Economic basis of the social value attributed to people

Cette thèse a pour but d’aller « à la racine » de la théorie de la valeur sociale (Beauvois & Dubois, 2009) stipulant que les adjectifs de personnalité ont pour fonction d’évaluer les agents sociaux. Nous montrons que les personnes sont évaluées sur ces adjectifs en fonction de l’utilité économique de leurs professions ou des conséquences économiques de leurs comportements, bien indépendamment de leurs qualités psychologiques. Nos travaux ont d’abord permis (études 1 à 4) d’appuyer l’intérêt de dégager trois registres de traits de personnalité (effort, compétence et aisance) qui évaluent trois niveaux distincts d’utilité. Nos études 5 à 8 précisent que la présence ou non d’objectifs économiques détermine le registre le plus utile pour juger la valeur sociale des personnes. L’aisance est décisive si les situations sont imprégnées d’objectifs économiques comme c’est le cas en entreprise. C’est sur ce modèle que les gens jugent par défaut. Dans les contextes où ces objectifs sont nettement absents, l’aisance est moins décisive que les autres registres. Une autre série d’études (9 et 10) montre que la simple connaissance des retombées économiques d’une réussite ou d’un échec, mêmes si ces retombées ne concernent pas directement l’auteur de la performance, a des effets sur la description qu’il fait de lui-même. Enfin, les dernières études (11 à 13) ont montré que les enjeux économiques impactent de nombreux phénomènes psychologiques (estime de soi, perception du caractère figé des traits et motivation scolaire). Finalement, nos travaux mettent en évidence l’intérêt de la prise en compte des objectifs économiques dans l’étude du jugement social.Our aim was to go "at the root" of the theory of social value (Beauvois & Dubois, 2009) stipulating that the adjectives of personality have the function of evaluating social agents. We show that people are evaluated on these adjectives according to the economic utility of their professions or the economic consequences of their behavior, regardless of their psychological qualities. Our work has first allowed (studies 1 to 4) to support the interest of identifying three registers of personality traits (effort, competence and agency) that evaluate three distinct levels of utility. Our studies 5 to 8 specify that the presence or absence of economic objectives determines the most useful register to judge the social value of people. Agency is decisive if the situations are imbued with economic objectives as is the case in company. It is on this model that people judge by default. In contexts where these objectives are clearly absent, agency is less decisive than the other registers. Another series of studies (9 and 10) shows that the mere knowledge of the economic benefits of a success or a failure, even if these effects do not directly concern the author of the performance, has effects on the description that he makes of himself. Finally, the latest studies (11 to 13) have shown that economic issues impact many psychological phenomena (self-esteem, perception of the fixed character of the traits and academic motivation). Finally, this PhD highlights the importance of taking into account economic objectives in the study of social judgment