Dataset Information

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.

ABSTRACT: Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high-fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueductal gray (vlPAG). In ob/ob mice, these alterations result in the following: (i) increased excitability of OX1-R-expressing vlPAG output neurons and subsequent increased OFF and decreased ON cell activity in the rostral ventromedial medulla, as assessed by patch clamp and in vivo electrophysiology; and (ii) analgesia, in both healthy and neuropathic mice. In HFD mice, instead, analgesia is only unmasked following leptin receptor antagonism. We propose that OX-A/endocannabinoid cross talk in the descending antinociceptive pathway might partly underlie increased pain thresholds in conditions associated with impaired leptin signaling.

SUBMITTER: Cristino L

PROVIDER: S-EPMC5130126 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.

Cristino Luigia L Luongo Livio L Imperatore Roberta R Boccella Serena S Becker Thorsten T Morello Giovanna G Piscitelli Fabiana F Busetto Giuseppe G Maione Sabatino S Di Marzo Vincenzo V

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150617 2

Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high-fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueducta ...[more]

PMID: 26081302

Similar Datasets

Project description:Osteoarthritis (OA) is a chronic joint disorder whose principal symptom is chronic pain. Current analgesics are inadequate and the mechanisms contributing to this pain are poorly understood but likely to include both local joint changes and central consequences. These studies used monoamine receptor agents combined with behavioral studies and single-unit dorsal horn recordings to examine whether descending noradrenergic and serotonergic inhibitions are altered in the monosodium iodoacetate model of OA pain, and whether increasing these inhibitions with the serotonin/noradrenaline reuptake inhibitor milnacipran can attenuate the attendant hypersensitivity. Early and late in the course of this model, milnacipran (s.c.) reduced behavioral hypersensitivity, and inhibited evoked responses from sensitized dorsal horn neurons. In naïve animals and the early, but not late, phase of the model, spinal administration of the ?(2)-adrenoceptor antagonist atipamezole fully reversed this neuronal inhibition, whereas atipamezole administered alone revealed that endogenous noradrenergic inhibition was reduced in the late phase. Blocking spinal 5-hydroxytryptamine-7 receptors with (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride suggested that the effects of milnacipran in the late phase were partly mediated by these receptors, and that descending serotonergic inhibition was increased in this phase. An opioidergic mechanism behind the effects of milnacipran was indicated by a partial reversal of these effects with naloxone. These studies demonstrate antinociceptive effects for milnacipran in a model of OA pain, whose effects come via descending serotonergic and noradrenergic, as well as opioidergic, pathways. Variations in the activity of these pathways over the course of this model may contribute to the presence of behavioral hypersensitivity and determine through which endogenous systems milnacipran exerts its effects.

Project description:Objectives: This paper aims to determine if hypnotic analgesia suggestion and transcranial direct-current stimulation (tDCS) have a differential effect on pain perception. We hypothesized that transcranial direct-current stimulation would be more effective than hypnotic analgesia suggestion at changing the descending pain modulating system, whereas the hypnotic suggestion would have a greater effect in quantitative sensory testing. Design: This is a randomized, double blind and crossover trial. Settings: All stages of this clinical trial were performed at the Laboratory of Pain and Neuromodulation of the Hospital de Clínicas de Porto Alegre. Subjects: Were included 24 healthy females aged from 18 to 45 years old, with a high susceptibility to hypnosis, according to the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C (15). Methods: The subjects received a random and crossover transcranial direct-current stimulation over the dorsolateral prefrontal cortex (2 mA for 20 min) and hypnotic analgesia (20 min). Results: Only hypnotic suggestion produced changes that are statistically significant from pre- to post-intervention in the following outcomes measures: heat pain threshold, heat pain tolerance, cold pressure test, and serum brain-derivate-neurotrophic-factor. The analysis showed a significant main effect for treatment (F = 4.32; P = 0.04) when we compared the delta-(Δ) of conditioned pain modulation task between the transcranial direct-current stimulation and hypnotic suggestion groups. Also, the change in the brain-derivate-neurotrophic-factor was positively correlated with the conditioned pain modulation task. Conclusion: The results confirm a differential effect between hypnotic suggestion and transcranial direct-current stimulation on the pain measures. They suggest that the impact of the interventions has differential neural mechanisms, since the hypnotic suggestion improved pain perception, whereas the transcranial direct-current stimulation increased inhibition of the descending pain modulating system. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03744897. Perspective: These findings highlight the effect of hypnotic suggestion on contra-regulating mechanisms involved in pain perception, while the transcranial direct-current stimulation increased inhibition of the descending pain modulating system. They could help clinicians comprehend the mechanisms involved in hypnotic analgesia and transcranial direct-current stimulation and thus may contribute to pain and disability management.

Dataset Information

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.

Publications

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure