Role of brainstem GABAergic signaling in central cannabinoid
receptor evoked sympathoexcitation and pressor responses in
Badr Mostafa Ibrahim, Abdel A. Abdel-Rahman
Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
ARTICLE INFO ABSTRACT
Accepted 22 July 2011
Available online 28 July 2011
The mechanisms implicated in the sympathoexcitation and pressor responses elicited by
R 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 (CB
R) 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 CB
R-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
R by i.c AM251 (30 μg/rat) or (ii) activation of central GABA
(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
R-evoked sympathoexcitation/pressor response in conscious rats.
© 2011 Elsevier B.V. All rights reserved.
BRAIN RESEARCH 1414 (2011) 1– 9
⁎ Corresponding author at: Department of Pharmacology and Toxicology, School of Medicine, East Carolina University, Greenville,
NC 27858, USA. Fax: +1 252 744 3203.
E-mail address: ABDELRAHMANA@ecu.edu (A.A. Abdel-Rahman).
Abbreviations: AM251, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; BP, blood
R, Cannabinoid receptor 1; DMSO, dimethylsulfoxide; HR, heart rate; MAP, mean arterial pressure; NE, norepinephrine;
RVLM, rostral ventrolateral medulla; WIN55,212-2, (R)-(+)-[2,3-Dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-
(1-naphthalenyl) methanone mesylate salt
0006-8993/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
available at www.sciencedirect.com