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 CB 1R 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 1R) 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 1R-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 CB 1R by i.c AM251 (30 μg/rat) or (ii) activation of central GABA AR 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 CB 1R-evoked sympathoexcitation/pressor response in conscious rats.