title: 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.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
authors.affiliation: Endocannabinoid Research Group, Division of Pharmacology 'L. Donatelli', Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.affiliation: Endocannabinoid Research Group, Division of Pharmacology 'L. Donatelli', Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Boccella
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Section of Physiology and Psychology, Department of Neurological and Movement Sciences (DSNM), University of Verona, Verona, Italy.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Becker
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Section of Physiology and Psychology, Department of Neurological and Movement Sciences (DSNM), University of Verona, Verona, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Morello
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: Section of Physiology and Psychology, Department of Neurological and Movement Sciences (DSNM), University of Verona, Verona, Italy.|National Institute of Neuroscience, Verona, Italy.
authors.forename: Giuseppe
authors.identifier: http://orcid.org/0000-0003-4281-8081
authors.initials: G
authors.lastname: Busetto
authors.affiliation: Endocannabinoid Research Group, Division of Pharmacology 'L. Donatelli', Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008820:Mice, Obese; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D059226:Nociceptive Pain / Q000473:pathology / Q000503:physiopathology*; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins / Q000378:metabolism*; D058748:Pain Perception / Q000502:physiology*; D010487:Periaqueductal Gray / Q000473:pathology / Q000503:physiopathology; D046509:Tissue Culture Techniques
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; C497459:Hcrtr1 protein, mouse; D020738:Leptin; D064446:Orexin Receptors; D000068797:Orexins; C094503:glyceryl 2-arachidonate