• Sabatino Maione, Fabiana Piscitelli, Luisa Gatta, Daniela Vita, Luciano De Petrocellis, Enza Palazzo, Vito de Novellis, and Vincenzo Di Marzo.
• Endocannabinoid Research Group, Department of Experimental Medicine - Division of Pharmacology 'L. Donatelli', Second University of Naples, Naples, Italy.
• Br. J. Pharmacol. 2011 Feb 1; 162 (3): 584-96.

Background And PurposeTwo non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception.Experimental ApproachElectrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey.Key ResultsCannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB(1) adenosine A(1) and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD.Conclusions And ImplicationsCBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action.© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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