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1 Pharmacological studies have suggested that A3 receptors are present on central neurons. Recently this adenosine receptor subtype has been identified in the rat and its presence in the central nervous system has been confirmed. 2 In this study we investigated the effects of acute intracerebroventricular (i.c.v.) injections of N6-2-(4-aminophenyl)-ethyladenosine (APNEA), a non-selective A3 adenosine receptor agonist, on arterial blood pressure (ABP) and heart rate (HR), after treatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of A1 adenosine receptors. 3 Anaesthetized rats, after DPCPX (12 μg−1 kg i.c.v.), were treated with APNEA (0.4–4 μg kg−1 i.c.v.) resulting in a transitory and dose-dependent decrease in arterial blood pressure without a change in heart rate. APNEA also induced hypotensive responses after i.c.v. pretreatment with aminophylline, at a dose of 20 μg kg−1. In contrast, pretreatment 48 h before, with 4 μg kg−1 i.c.v. of pertussis toxin reduced the hypotensive effect induced by APNEA. Administration of APNEA at a higher dose (20 μg kg−1 i.c.v.), after DPCPX, induced a decrease in ABP of −66±5.4 mmHg and after 3 min a decrease in heart rate of −62±6.0 beats min−1. Transection of the spinal cord abolished this significant fall in ABP, but not the decrease of HR. 4 These results suggest that a population of A3-receptors is present in the CNS, whose activation induces a decrease in blood pressure with no change of heart rate. British Journal of Pharmacology (1998) 125, 437–440; doi:10.1038/sj.bjp.0702126

Two 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.Electrical 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.Cannabidiol 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.CBD 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.