Research reportThe endocannabinoid, endovanilloid and nitrergic systems could interact in the rat dorsolateral periaqueductal gray matter to control anxiety-like behaviors

- AEA induces biphasic effects in the modulation of anxiety-like behaviors in the dlPAG.
- AEA induces an anxiolytic-like effect in the dlPAG at lower doses.
- The lost of AEA anxiolytic-like effect at higher doses is influenced by NO formation.
- Concomitant NO formation and TRPV1 activation facilitates defensive responses.

Cannabinoid compounds usually produce biphasic effects in the modulation of emotional responses. Low doses of the endocannabinoid anandamide (AEA) injected into the dorsolateral periaqueductal gray matter (dlPAG) induce anxiolytic-like effects via CB1 receptors activation. However, at higher doses the drug loses this effect, in part by activating Transient Receptor Potential Vanilloid Type 1 (TRPV1). Activation of these latter receptors could induce the formation of nitric oxide (NO). Thus, the present study tested the hypothesis that at high doses AEA loses it anxiolytic-like effect by facilitating, probably via TRPV1 receptor activation, the formation of NO. Male Wistar rats received combined injections into the dlPAG of vehicle, the TRPV1 receptor antagonist 6-iodo-nordihydrocapsaicin or the NO scavenger carboxy-PTIO (c-PTIO), followed by vehicle or AEA, and were submitted to the elevated plus maze (EPM) or the Vogel conflict test (VCT). A low dose (5 pmol) of AEA produced an anxiolytic-like effect that disappeared at higher doses (50 and 200 pmol). The anxiolytic-like effects of these latter doses, however, were restored after pre-treatment with a low and ineffective dose of c-PTIO in both animal models. In addition, the combined administration of ineffective doses of 6-iodo-nordihydrocapsaicin (1 nmol) and c-PTIO (0.3 nmol) produced an anxiolytic-like response. Therefore, these results support the hypothesis that intra-dlPAG injections of high doses of AEA lose their anxiolytic effects by favoring TRPV1 receptors activity and consequent NO formation, which in turn could facilitate defensive responses.