Enhancement of the Rostral Ventrolateral Medulla ERK1/2/nNOS/NO Signaling Pathway is Implicated in the Central Cannabinoid Receptor‐Evoked Sympathoexcitation in Conscious Rats

Reported studies have shown that activation of CB1R in the rostral ventrolateral medulla (RVLM) of anaesthetized animals results in sympathoexcitation/pressor response; yet, the exact signaling mechanisms are unknown. Moreover, it has been shown that phosphorylation of molecular targets ERK 1/2 and nNOS (p‐ERK1/2 and p‐nNOS), which led to NO release underlies wide array of CB1R‐evoked pharmacological actions. Therefore, this study aimed to elucidate the role of p‐ERK1/2‐p‐nNOS‐NO signaling in the central CB1R‐mediated sympathoexcitation. We have simultaneously measured RVLM‐NO levels in real‐time (in vivo electrochemistry), blood pressure and heart rate following unilateral intra‐RVLM microinjection of CB1R agonist [(R)‐(+)‐[2,3‐Dihydro‐5‐methyl‐ 3[(4‐morpholinyl)methyl]pyrrolo[1,2,3‐de]‐1,4‐benzoxazinyl]‐(1‐naphthalenyl) methanone mesylate salt] WIN55212‐2 (100, 200 or 300 pmol/80nL, n=5) in conscious rats. WIN55212‐2 elicited dose dependent increases in blood pressure and RVLM‐NO levels (n=5, P <0.05). The vehicle of WIN55212‐2 had no effect on the measured variables. Additionally, ERK1/2 and nNOS phosphorylation was significantly higher in the injected RVLM compared to control (n=4, P < 0.05). These findings provide new insight into molecular mechanisms that underlie the central CB1R‐evoked pressor effects.