biostudies-literatureUnknown41(2)Cristino LPain 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; andNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology508-20https://www.ebi.ac.uk/biostudies/studies/S-EPMC5130126biostudies-literatureOrexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.PMC5130126Di Marzo VLuongo LImperatore RMaione SBoccella SBecker TCristino LPiscitelli FBusetto GMorello GfalseOrexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency.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; and2016-01-01T00:00:00Z2016 Jan2025-05-29T19:22:00.033Z2025-05-29T19:22:00.033ZS-EPMC51301262608130210.1038/npp.2015.173