title: Microinjection of orexin-A into the rat locus coeruleus nucleus induces analgesia via cannabinoid type-1 receptors.
abstract: Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation. LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors. Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors. In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain. Pain was induced by formalin (2%) injection into the hind paw. Intra-LC microinjection of orexin-A decreased the nociception score during both phases of formalin test. Furthermore, intra-LC microinjection of either SB-334867 (OX1 receptor antagonist) or AM251 (CB1 receptor antagonist) increased flinches and also the nociception score during phase 1, 2 and the inter-phase of formalin test. The analgesic effect of orexin-A was diminished by prior intra-LC microinjection of either SB-334867 or AM251. This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test. Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A. These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Mohammad-Pour Kargar
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Azizi
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Javad
authors.initials: J
authors.lastname: Mirnajafi-Zadeh
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Mani
authors.initials: M
authors.lastname: Ali Reza
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address: ssemnan@modares.ac.ir.
authors.forename: Saeed
authors.initials: S
authors.lastname: Semnanian
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000633:toxicity; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008845:Microinjections; D009287:Naphthyridines; D000068797:Orexins / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D000700:Analgesics; D001583:Benzoxazoles; D002352:Carrier Proteins; C540799:Cnrip1 protein, rat; D009287:Naphthyridines; D000068797:Orexins; D010880:Piperidines; D011720:Pyrazoles; D005557:Formaldehyde; C103505:AM 251; D014508:Urea
keywords: AM251; Endocannabinoid; Formalin test; Locus coeruleus nucleus; Orexin; Rat; SB-334867