The cannabinoid receptor antagonist SR-141716A induces penile erection in male rats: Involvement of paraventricular glutamic acid and nitric oxide

Abstract

The cannabinoid CB1 receptor antagonist SR141716A (0.5, 1 and 2 μg) induces penile erection when injected into the paraventricular nucleus of male rats. The pro-erectile effect of SR 141716A occurs concomitantly with an increase in the concentration of NO 2 − and NO 3 − in the paraventricular dialysate obtained by means of intracerebral microdialysis. Both penile erection and NO 2 − increase induced by SR 141716A were reduced by the prior injection into the PVN of the cannabinoid CB1 agonists WIN 55,212-2 (5 μg) or HU 210 (5 μg), given into the paraventricular nucleus at doses unable to induce penile erection or to modify NO 2 − concentration. SR 141716A responses were also reduced by nitro- l-arginine methylester (20 μg), a non-selective NO synthase inhibitor, S-methyl- l-thiocitrulline (20 μg), a selective neuronal NO synthase inhibitor, the excitatory amino acid NMDA receptor antagonist dizocilpine ((+)MK 801) (1 μg), or the GABA A receptor agonist muscimol (0.2 μg) injected into the PVN 15 min before SR 141716A. In contrast, the inducible NO synthase inhibitor l-N(6)-(1-iminoethyl)lysine (20 μg), the GABA B receptor agonist baclofen (0.2 μg), the mixed dopamine receptor antagonist cis-flupenthixol (10 μg), and the oxytocin receptor antagonist d(CH 2) 5Tyr(Me)-Orn 8-vasotocin (1 μg), were ineffective. Despite its inability to reduce penile erection and NO 2 − increase induced by SR 141716A when injected into the PVN, d(CH 2) 5Tyr(Me)-Orn 8-vasotocin (1 μg) reduced almost completely penile erection without reducing paraventricular NO 2 − increase when injected into the lateral ventricles 15 min before SR 141716A. The present results show that SR 141716 induces penile erection by a mechanism (possibly activation of excitatory amino acid neurotransmission), which causes the activation of neuronal NO synthase in paraventricular oxytocinergic neurons mediating penile erection.