Emotional response induced by salvinorin a and Δ9–tetrahydrocannabinol (THC) is mediated by κ-opioid and CB1 cannabinoid receptor in rats

Daniela Braida, Valeria Capurro, Alessia Zani, Mariaelvina Sala. University Of Milan, Milan, Italy, United States.

Salvinorin A, a potent κ-opioid receptor agonist (Roth et al., 2002), is the major active ingredient of Salvia divinorum, the abuse of which has greatly increased in recent years for its hallucinogenic effects. Recently, salvinorin A has been shown to produce, in the zebrafish, CB1 cannabinoid receptor mediated-reinforcing effects (Braida et al., 2007). Furthermore, salvinorin A, like THC, induced in humans both positive and negative emotional responses, depending on the dose and route of administration (Porter and Felder, 2001; Gonzalez et al., 2006).

The aim of the present work was to investigate salvinorin A, in comparison with THC, on emotional reactivity in male Sprague-Dawley rats (150-200 g) using the elevated plus-maze (EPM) and the forced swimming test (FST) apparatus at doses not affecting motor activity. Animals, divided in groups of 10 each, were acutely treated with Salvinorin A (0.001-1000 μg kg-1 s.c.) or THC (1.5-1500 μg kg-1 i.p.). Anxiety-like response was studied in EPM apparatus according to Pellow et al. (1985). The test length was 5 min. The total time spent in each arm and the number of arm entries were scored 20 min after salvinorin A and 30 min after THC treatment. Depression was evaluated in the FST (Porsolt, 1979) consisting in two swimming sessions where the time of immobility, during the 2nd 5-min session, was an indicator of antidepressant activity. The obtained results were expressed as mean (± SEM) and statistically analysed by one-way ANOVA or Kruskal-Wallis test followed by appropriate post-hoc test.

Salvinorin A and THC showed a significant dose-dependent increase in the mean number of entries and time spent in the open arms and a decrease of the mean time spent in immobility. The maximal anxiolytic effect was obtained with the dose of 0.1 μg kg-1 of salvinorin A and 750 μg kg-1 of THC, while the maximal antidepressant effect was obtained with 10 μg kg-1 of salvinorin A and 75 μg kg-1 of THC. Pre-treatment with the CB1 cannabinoid receptor antagonist, AM 251 (3 mg kg-1 i.p. -40 min), and the κ opioid antagonist, nor-binaltorphimine (10 mg kg-1 i.p. –120 min), significantly blocked both the anxiolytic and antidepressant effects induced by salvinorin A and THC.

The present findings support the demonstration of a mechanism which is cannabinoid CB1 and κ-opioid receptor-mediated for the emotional response induced by both salvinorin A and THC.

Braida D. et al. (2007) Psychopharmacology 190:441-448

Gonzalez D. et al. (2006) Drug Alcohol Depend. 85:157-182

Pellow S. et al. (1985) J Neurosci Methods 14:149-167

Porsolt R.D. (1979) Biomedicine 30:139-140

Porter A.C. and Felder C.C. (2001) Pharmacol Ther 90: 45– 60

Roth B.L. et al. (2002) Proc. Natl. Acad. Sci. USA 99:11934-11939