Ocytocine, Douleur et Emotions

National audienceL’ocytocine a longtemps été associée au comportement maternel avec son impli-cation dans l’accouchement, l’allaitement ou encore l’attachement mère-enfant. Or, denombreuses études montrent aujourd’hui que l’ocytocine joue un rôle majeur dans le contrôlede nombreuses autres fonctions physiologiques, allant des comportements sexuels complexesqui lui valent souvent le surnom de « molécule de l’amour », jusqu’à la régulation complexedes émotions. Sont concernées les émotions à valence positive, initiées par la confiance en soiou les interactions sociales, ainsi que les émotions à valence négative, comme la peur ou, biensûr, la douleur. Pourtant, si l’on connaît à présent assez bien les effets de l’ocytocine, et quel’on commence à comprendre les circuits cellulaires à leur origine, la majorité des études sontmenées chez le rongeur, avec des inconnues majeures persistantes chez l’homme. Ainsi, nousprésenterons, au cours de cette revue non exhaustive, les effets régulateurs de l’ocytocine surles émotions et tenterons d’y porter un regard critique.© 2018 Elsevier Masson SAS. Tous droits r´eserv´es

L'ocytocine, peptide aux multiples facettes

Accouchement, naissance, attachement parents-enfant : quiconque s’y intéresse a entendu parler de cette molécule à tout faire, l’ocytocine, surnommée hormone de l’amour. Invitation est faite à découvrir ce petit peptide

Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms

Abstract Fast Inhibitory controls mediated by glycine (GlyRs) and GABAA receptors (GABAARs) play an important role to prevent the apparition of pathological pain symptoms of allodynia and hyperalgesia. The use of positive allosteric modulators of these receptors, specifically expressed in the spinal cord, may represent an interesting strategy to limit or block pain expression. In this study, we have used stereoisomers of progesterone metabolites, acting only via non-genomic effects, in order to evaluate the contribution of GlyRs and GABAARs for the reduction of mechanical and thermal heat hypernociception. We show that 3a neurosteroids were particularly efficient to elevate nociceptive thresholds in naive animal. It also reduced mechanical allodynia and thermal heat hyperalgesia in the carrageenan model of inflammatory pain. This effect is likely to be mediated by GABAA receptors since 3b isomer was inefficient. More interestingly, 3a5b neurosteroid was only efficient on mechanical allodynia while having no effect on thermal heat hyperalgesia. We characterized these paradoxical effects of 3a5b neurosteroid using the strychnine and bicuculline models of allodynia. We clearly show that 3a5b neurosteroid exerts an antinociceptive effect via a positive allosteric modulation of GABAARs but, at the same time, is pronociceptive by reducing GlyR function. This illustrates the importance of the inhibitory amino acid receptor channels and their allosteric modulators in spinal pain processing. Moreover, our results indicate that neurosteroids, which are synthesized in the dorsal horn of the spinal cord and have limited side effects, may be of significant interest in order to treat pathological pain symptoms.

Design considerations for a low-noise CMOS image sensor

This paper reports a Low-Noise CMOS Image Sensor. Low-noise operation is achieved owing to the combination of a noise-enhanced pixel, the use of a two-step ADC architecture and the analysis, and the optimization thereof, of the noise contributed by the readout channel. The paper basically gathers the sensor architecture, the ADC converter architecture, the outcome of the noise analysis and some basic characterization data. The general low-noise design framework is discussed in the companion presentation.Junta de Andalucía TIC 2012-2338Office of Naval Research (USA) N00014141035

TRP channels and monoterpenes: Past and current leads on analgesic properties

The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member 8 (TRPM8), the TRP vanilloid 1 (TRPV1), and the TRP ankyrin 1 (TRPA1) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia effects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, offer an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions

Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

<p>Abstract</p> <p>Background-</p> <p>Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission.</p> <p>Results-</p> <p>In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice.</p> <p>Conclusions-</p> <p>Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.</p

Long-lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone synthesis which potentiates GABA(A) receptor-mediated synaptic inhibition.

Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in inflammatory and neuropathic conditions. However, cellular and molecular mechanisms underlying OT spinal antinociception are still poorly understood. In this study, we used biochemical, electrophysiological, and behavioral approaches to demonstrate that OT levels are elevated in the spinal cord of rats exhibiting pain symptoms, 24 h after the induction of inflammation with an intraplantar injection of λ-carrageenan. Using a selective OT receptor antagonist, we demonstrate that this elevated OT content is responsible for a tonic analgesia exerted on both mechanical and thermal modalities. This phenomenon appeared to be mediated by an OT receptor-mediated stimulation of neurosteroidogenesis, which leads to an increase in GABA(A) receptor-mediated synaptic inhibition in lamina II spinal cord neurons. We also provide evidence that this novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases, ERK1/2, after OT receptor activation. The oxytocinergic inhibitory control of spinal pain processing is emerging as an interesting target for future therapies since it recruits several molecular mechanisms, which are likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.journal articleresearch support, non-u.s. gov't2013 Oct 16importe

Neuropeptidergic modulation of emotions

Neuroscience

Exploration fonctionnelle de la douleur et de sa modulation spinale chez le rongeur

L'évaluation des douleurs en expérimentation animale se heurte classiquement, quelle que soit la technique employée à la subjectivité de l'expérimentateur. Afin de permettre une meilleure compréhension des mécanismes nociceptifs et une prise en charge plus adéquate des douleurs, il est alors nécessaire de développer des outils d'évaluation objective des douleurs. En premier lieu, j ai validé deux nouveaux tests d'évaluation de la douleur chez l'animal non contraint : la plaque chaude / froide dynamique pour mesurer de manière concomitante l'hyperalgésie et l'allodynie, l'incapacitance dynamique pour apprécier le déficit postural de l'animal. Puis, la radiotélémétrie m a permis de mesurer la température, le rythme cardiaque et l'activité locomotrice en continu chez l'animal libre de ses mouvements. J ai ainsi détecté les altérations physiologiques associées à un épisode douloureux spontané. De plus, j ai développé et validé un modèle de douleur post-opératoire persistante, qui a permis de mettre en évidence une analgésie préventive par la ropivacaïne. Enfin, j ai étudié la modulation spinale de l'influx nociceptif par les neurostéroïdes, en illustrant l'importance de l'inhibition GABA- et glycinergique dans ce processus, et en montrant l'implication de la neurostéroïdogenèse spinale endogène dans l'effet anti-douleur du contrôle inhibiteur ocytocinergique. Ce travail se traduit par l'accès à de nouveaux outils d'évaluation de la douleur chez l'animal non contraint, l'utilisation de la radiotélémétrie dans l'étude des altérations physiologiques liées à la douleur chez l'animal libre de ses mouvements, et une meilleure compréhension du rôle des neurostéroïdes endogènes spinauxPain evaluation in animal experimentation always encountered a limit in the subjectivity of the researcher. In order to allow both better understanding of the nociceptive mechanisms and care of painful patients, it is useful to develop new and objective tools for pain evaluation. Firstly, I validated two new protocols of pain evaluation used on unrestrained animals: dynamic hot/cold plate in order to measure simultaneously hyperalgesia and allodynia, and dynamic weight bearing in order to monitor the postural impairment of the animal. Then, I used radiotelemetry to continuously record body temperature, heart rate and locomotor activity in frely moving animals. Thus, I detected the physiological alterations associated with a spontaneous painful event. Moreover, I developed and validated a new postoperative pain model which have allows demonstrating the preventive analgesia effect of ropivacaine. Finally, I studied the spinal modulation by neurosteroids of nociceptive signal through their relative impact of GABA- and glycinergic inhibition. Furthermore, I showed the implication of spinal endogenous neurosteroidogenesis in the analgesic effect of oxytocin inhibitory control. This work lead to new tools for pain evaluation in unrestrained animals, to the use of the radiotelemetry in the evaluation of pain associated symptoms in frely moving animals, and to a better understanding of the role of spinal endogenous neurosteroids in pain processing