title: Role of brainstem GABAergic signaling in central cannabinoid receptor evoked sympathoexcitation and pressor responses in conscious rats.
abstract: The mechanisms implicated in the sympathoexcitation and pressor responses elicited by central CB₁R activation are not fully understood. Further, the few reported mechanistic studies on this endeavor were conducted in anesthetized rats. Therefore, it was important to identify the dose-related cardiovascular responses elicited by central administration of the cannabinoid receptor (CB₁R) agonist WIN55,212-2 in conscious rats. The second and main objective of the study was to test the hypothesis that brainstem GABAergic transmission is implicated in the CB₁R-evoked sympathoexcitation/pressor response. In conscious rats, intracisternal (i.c) WIN55,212-2 (3, 10, 30 μg/rat) elicited dose-dependent increases in mean arterial pressure (MAP) and plasma norepinephrine (NE; index of sympathoexcitation), and reduced heart rate (HR). Subsequent neurochemical studies showed that i.c WIN55,212-2 (15 μg/rat) significantly increased the number and percentage of neurons that exhibited dual immunostaining for tyrosine hydroxylase (catecholaminergic neurons) and c-Fos (marker of neuronal activity) within the rostral ventrolateral medulla, which suggests enhanced central sympathetic tone. These neurochemical responses along with the increases in MAP and plasma NE were drastically attenuated by prior: (i) blockade of central CB₁R by i.c AM251 (30 μg/rat) or (ii) activation of central GABA(A)R by i.c muscimol (0.1 μg/rat). Collectively, these neurochemical and cardiovascular findings are the first to suggest a pivotal role for the inhibition of brainstem GABAergic transmission in the central CB₁R-evoked sympathoexcitation/pressor response in conscious rats.
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA.
authors.forename: Badr Mostafa
authors.initials: BM
authors.lastname: Ibrahim
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D009025:Morpholines / Q000008:administration & dosage; D009118:Muscimol / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood*; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D058785:GABA-A Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D009118:Muscimol; C103505:AM 251; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine