title: A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats.
abstract: Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. Here, we tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R following intracisternal (i.c.) WIN55,212-2 (15μg/rat) in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response because (i) selective blockade of central CB1R (AM251, 30μg/rat; i.c.) abrogated WIN55,212-2-evoked increases in RVLM orexin-A level, (ii) the selective OX1R antagonist SB-408124 (10nmol/rat; i.c.) attenuated orexin-A (3nmol/rat; i.c.) or WIN55,212-2 (15μg/rat; i.c.)-evoked pressor response while selective CB1R blockade (AM251) had no effect on orexin-A (3nmol/rat; i.c.)-evoked pressor response, (iii) direct CB1R activation in the RVLM (WIN55,212-2; 0.1μg/rat) increased RVLM orexin-A and BP. Finally, SB-408124 attenuated WIN55,212-2-evoked increases in RVLM nNOS and ERK1/2 phosphorylation and BP. Our findings suggest that orexin-A/OX1R dependent activation of the RVLM nNOS/ERK1/2 cascade is essential neurochemical mechanism for the central CB1R-mediated pressor response in conscious rats.
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858, United States.
authors.forename: Badr Mostafa
authors.initials: BM
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858, United States. Electronic address: ABDELRAHMANA@ecu.edu.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins / Q000008:administration & dosage / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D002317:Cardiovascular Agents; C543264:Cnr1 protein, rat; C000596232:Hcrt protein, rat; C578627:Hcrtr1 protein, rat; D009025:Morpholines; D009281:Naphthalenes; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D010671:Phenylurea Compounds; D043884:Receptor, Cannabinoid, CB1; C542397:SB 408124; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D014446:Tyrosine 3-Monooxygenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Blood pressure; Cannabinoid receptor 1; Orexin receptor 1; Rostral ventrolateral medulla