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 (OX 1 R) signaling is implicated in cannabinoid receptor 1 (CB 1 R) modulation of feeding. Further, our studies established the dependence of the central CB 1 R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. We tested the novel hypothesis that brainstem orexin-A/OX 1 R signaling plays a pivotal role in the central CB 1 R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB 1 R, OX 1 R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB 1 R following intracisternal (i.c.) WIN55,212-2 (15 µg/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 CB 1 R-mediated pressor response because (i) selective blockade of central CB 1 R (AM251, 30 µg/rat; i.c.) abrogated WIN55,212-2-evoked increases in RVLM orexin-A level, (ii) the selective OX 1 R antagonist SB-408124 (10 nmol/rat; i.c.) attenuated orexin-A (3 nmol/rat; i.c.) or WIN55,212-2 (15 µg/rat; i.c.)-evoked pressor response while selective CB 1 R blockade (AM251) had no effect on orexin-A (3 nmol/rat; i.c.)-evoked pressor response, (iii) direct CB 1 R activation in the RVLM (WIN55,212-2; 0.1 µg/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/OX 1 R dependent activation of the RVLM nNOS/ERK1/2 cascade is essential neurochemical mechanism for the central CB 1 R-mediated pressor response in conscious rats.

Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?

“…CB 1 receptors were detected in high densities in many brain regions of humans and experimental animals [ 92 ]. They also occur in brain regions involved in cardiovascular regulation, including the rostral ventrolateral medulla (RVLM; [ 93 , 94 ]), the bed nucleus of the stria terminalis (BNST; [ 95 , 96 ]), the ventral medial prefrontal cortex (vMPFC; [ 97 ]), the paraventricular nucleus of the hypothalamus (PVN; [ 98 ]), the nucleus tractus solitarii (NTS; [ 99 ]) and the dorsal periaqueductal gray (dPAG; [ 97 , 100 ]).…”

Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control

“…While a cardioprotective role for endocannabinoids (ECs) might seem unreasonable because current knowledge implicates ECs in diabetes-induced inflammation, oxidative stress, and cardiovascular dysfunction (Horvath et al, 2012), we must consider other important findings. First, the detrimental cardiovascular effects of ECs are mostly mediated by the cannabinoid receptor 1, CB1R (Ibrahim and Abdel-Rahman, 2015; Rajesh et al, 2012; Varga et al, 1995). Second, activation of the novel EC receptor, GPR18, by its endogenous (N-arachidonylglycine; NAGly) (Burstein et al, 2011; Kohno et al, 2006) or synthetic (trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; abn-cbd) ligand causes hypotension (Offertaler et al, 2003; Parmar and Ho, 2010).…”

Inhibition of anandamide hydrolysis does not rescue respiratory abnormalities observed in an animal model of Parkinson's disease

“…In addition, central activation of CB1 receptors can increase blood pressure along with an increase in the content of orexin A in the rostral ventrolateral medulla. High levels of orexin in rats are associated with higher levels of arousal, which, in turn, can stimulate the breathing process (Ibrahim & Abdel‐Rahman, 2015; Nattie & Li, 2012).…”