Ž . European Journal of Pharmacology 391 2000 151–161 www.elsevier.nlrlocaterejphar Pharmacological characterisation of cannabinoid CB receptors in 1 the rat and mouse Lucy Lay, James A. Angus, Christine E. Wright ) Department of Pharmacology, UniÕersity of Melbourne, ParkÕille, Victoria 3010, Australia Received 11 November 1999; received in revised form 11 January 2000; accepted 18 January 2000 Abstract The role of cannabinoid CB receptors in sympathetic neurotransmission was characterised in nerve-mediated responses of isolated 1 right atria, vasa deferentia and small mesenteric resistance arteries using the cannabinoid CB receptor agonists D 9 -tetrahydrocannabinol, 1 CP 55,940 and anandamide and the cannabinoid CB -selective antagonist SR 141716A. In the mouse vas deferens, the twitch response 1 was completely inhibited by each of the putative cannabinoid receptor agonists with pIC values of CP 55,940, 9.2 "0.1; D 9 -tetrahydro- 50 cannabinol, 8.4 "0.1; anandamide, 7.1 "0.1. SR 141716A 10–100 nM was a competitive antagonist of all three agonists with a p K B Ž . value of 8.4–8.6, consistent with an interaction at the cannabinoid CB receptor. In the rat vas deferens CP 55,940 0.01–10 mM 1 Ž . 9 inhibited the contractions to a significant extent 88.5 "0.5% at 10 mM; pIC of 7.1 "0.1 while D -tetrahydrocannabinol and 50 Ž . anandamide both up to 10 mM were inactive. CP 55,940 exhibited low potency in rat compared with mouse vas deferens and the rat Ž . Ž . concentration–response curve was not competitively antagonised by SR 141716A 100 nM or SR 144528 10 nM–10 mM , suggesting Ž. an interaction at a receptor s distinct from cannabinoid CB or CB . Sympathetic nerve-induced tachycardia in rat and mouse atria, and 1 2 rat mesenteric artery smooth muscle contractile responses to perivascular nerve stimulation, were not inhibited by D 9 -tetrahydrocanna- binol, CP 55,940 or anandamide up to 1 mM. These data indicate that cannabinoid CB receptor activation inhibits sympathetic 1 neurotransmission only in the mouse vas deferens and thus point to species and regional differences in cannabinoid CB receptor 1 involvement in pre-synaptic inhibition of sympathetic neurotransmission and CP 55,940 may have inhibitory actions in rat vas deferens unrelated to cannabinoid receptor activity. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Cannabinoid CB receptor; D 9 -Tetrahydrocannabinol; CP 55,940; Anandamide; SR 141716A; SR 144528; Sympathetic neurotransmission 1 1. Introduction Interest in cannabinoid pharmacology has developed since the discovery of both cannabinoid receptors and the Ž endogenous ligand, anandamide Devane et al., 1988, 1992; . Munro et al., 1993 . Two cannabinoid receptor subtypes, the CB and CB have been characterised. Cannabinoid 1 2 CB receptors are located predominantly in the central 1 nervous system but are also present pre-junctionally on some peripheral autonomic nerves where they inhibit neurotransmitter release in the urogenital, gastrointestinal Ž and cardiovascular systems Mackie and Hille, 1992; Ishac . et al., 1996; Pertwee and Fernando, 1996 . ) Corresponding author. Tel.: q 61-3-9344-8219; fax: q 61-3-9344- 0241. Ž E-mail address: c.wright@pharmacology.unimelb.edu.au C.E. . Wright . Both D 9 -tetrahydrocannabinol and an endogenous mam- malian cannabinoid, anandamide, are naturally occurring cannabinoid receptor agonists. Anandamide is found both Ž . in the brain porcine and rat and in peripheral tissues such Ž as the rat kidney vasculature Devane et al., 1992; Deutsch . et al., 1997 and is physiologically regulated by fatty acid Ž . amide hydrolase activity Cravatt et al., 1996 . To date, many synthetic cannabinoid receptor agonists have been synthesised, including, CP 55,940, a potent, bicyclic Ž . cannabinoid receptor agonist Pertwee et al., 1993 . Most in vitro bioassays of the effects of cannabinoids Ž have been conducted in the mouse or guinea pig Ishac et al., 1996; Pertwee and Fernando, 1996; Pertwee et al., . 1996a,b . However, there is higher, albeit small, conserva- tion between rat and human cannabinoid CB mRNA than 1 Ž between mouse and human Chakrabarti et al., 1995; Shire . et al., 1996 . Therefore, it was of interest to compare functional responses caused by cannabinoid CB receptor 1 0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 00 00062-5