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.

• Authors: Luigia Cristino, Livio Luongo, Roberta Imperatore, Serena Boccella, Thorsten Becker, Giovanna Morello, Fabiana Piscitelli, Giuseppe Busetto, Sabatino Maione, Vincenzo Di Marzo
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 41 Issue 2 Pg. 508-20 (Jan 2016) ISSN: 1740-634X [Electronic] England
• PMID: 26081302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arachidonic Acids
• Endocannabinoids
• Glycerides
• Hcrtr1 protein, mouse
• Leptin
• Orexin Receptors
• Orexins
• glyceryl 2-arachidonate

Topics

• Animals
• Arachidonic Acids (metabolism)
• Disease Models, Animal
• Endocannabinoids (metabolism)
• Glycerides (metabolism)
• Leptin (metabolism)
• Male
• Membrane Potentials (physiology)
• Mice, Obese
• Neural Pathways (pathology, physiopathology)
• Neurons (pathology, physiology)
• Nociceptive Pain (pathology, physiopathology)
• Orexin Receptors (metabolism)
• Orexins (metabolism)
• Pain Perception (physiology)
• Periaqueductal Gray (pathology, physiopathology)
• Tissue Culture Techniques