title: Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray.
abstract: The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice. Intra-vlPAG (i.pag.) microinjection of orexin A in the mouse vlPAG increased the hot-plate latency. This effect was mimicked by i.pag. injection of WIN 55,212-2, a CB1 agonist, and antagonized by i.pag. injection of the antagonist of OX1 (SB 334867) or CB1 (AM 251), but not OX2 (TCS-OX2-29) or opioid (naloxone), receptors. [Ala(11), D-Leu(15)]-orexin B (i.pag.), an OX2 selective agonist, also induced antinociception in a manner blocked by i.pag. injection of TCS-OX2-29, but not SB 334867 or AM 251. Mice receiving restraint stress for 30 min showed significantly longer hot-plate latency, more c-Fos-expressing orexin neurons in the lateral hypothalamus and higher orexin levels in the vlPAG than unrestrained mice. Restraint SIA in mice was prevented by i.pag. or intraperitoneal injection of SB 334867 or AM 251, but not TCS-OX2-29 or naloxone. These results suggest that during stress, hypothalamic orexin neurons are activated, releasing orexins into the vlPAG to induce analgesia, possibly via the OX1 receptor-initiated, endocannabinoid-mediated disinhibition mechanism previously reported. Although activating either OX1 or OX2 receptors in the vlPAG can lead to antinociception, only OX1 receptor-initiated antinociception is endocannabinoid-dependent.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsin-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Lu-Yang
authors.initials: LY
authors.lastname: Chang
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Ho
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Teng
authors.affiliation: Department of Physiology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Hwang
authors.affiliation: Gill Center and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan; Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, Taiwan. Electronic address: lcchiou@ntu.edu.tw.
authors.forename: Lih-Chu
authors.initials: LC
authors.lastname: Chiou
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009287:Naphthyridines; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D064446:Orexin Receptors / Q000819:agonists / Q000378:metabolism*; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D000701:Analgesics, Opioid; D048588:Benzoxazines; D001583:Benzoxazoles; C578453:CNR1 protein, mouse; C497459:Hcrtr1 protein, mouse; D007546:Isoquinolines; D009025:Morpholines; D009281:Naphthalenes; D009287:Naphthyridines; C497461:OX2 protein, mouse; D064446:Orexin Receptors; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D009270:Naloxone; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D014508:Urea; D003345:Corticosterone
keywords: AM 251 (PubChem CID: 2125); Cannabinoid; OX1 and OX2 receptors; Orexin; Pain; Periaqueductal gray; SB 334867 (PubChem CID: 6604926); Stress-induced analgesia; TCS-OX2–29 (PubChem CID: 53302033); WIN 55,212-2 (PubChem CID: 5311501); morphine (PubChem CID: 5464110); naloxone (PubChem CID: 5464092); naltrexone (PubChem CID: 5485201)