Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat David A. Scott * , Christine E. Wright, James A. Angus The Department of Pharmacology, University of Melbourne, Melbourne, Vic. 3010, Australia Received 16 August 2003; received in revised form 3 December 2003; accepted 26 January 2004 Abstract The roles of the two cannabinoid receptor subtypes, CB-1 and CB-2, have not been clarified in cannabinoid-mediated analgesia. We investigated the efficacy of the non-selective cannabinoid receptor agonist CP55,940 in the modulation of responses in the rat to both acute pain (tail flick) and neuropathic pain (tactile allodynia following chronic L5/6 spinal nerve ligation). Responses were also assessed in the presence of the CB-1 antagonist SR141716A (SR1) and the CB-2 antagonist SR144528 (SR2). CP55,940 attenuated tactile allodynia (ED 50 0.04 mg/kg i.t. (95% CI 0.032 – 0.044 mg/kg), 0.12 mg/kg i.p. (95% CI 0.10 – 0.15 mg/kg)) and induced thermal antinociception (ED 50 tail flick 0.07 mg/kg i.t. (95% CI 0.05 – 0.10 mg/kg), 0.17 mg/kg i.p. (95% CI 0.11 – 0.26 mg/kg)). SR1 0.5 mg/kg i.t. attenuated the antinociceptive effect of CP55,940 in both modalities. However, SR1 1.0 mg/kg i.p. decreased tail flick latency but had no effect on tactile allodynia antinociception. In contrast, SR2 1.0 mg/kg i.p. significantly decreased the effect of i.p. CP55,940 on both tail flick antinociception and tactile allodynia ðP , 0:05Þ: The combination of SR1 and SR2 (i.p.) had an additive effect in decreasing the antinociception induced by CP55,940 on tail flick responses ðP , 0:005Þ: These results suggest a role for CB-2 receptor-mediated antinociception in both acute and neuropathic pain in addition to centrally located CB-1 mechanisms. q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Neuropathic pain; Cannabinoid; Antinociception; Analgesia; Antagonist; CB-1 receptor; CB-2 receptor 1. Introduction Cannabinoids are agonist ligands of the CB-1 and CB-2 receptors (Pertwee, 1997). The CB-1 receptor is predomi- nantly associated with the nervous system in supraspinal, spinal and possibly peripheral sites, and has a role in antinociception (Richardson, 2000). The CB-2 receptor has not been consistently identified in the central nervous system, and appears to be expressed on the surface of immune-responsive cells (Facci et al. 1995; Rice et al., 2002). The doses in which efficacy of CB-1 agonists have been demonstrated for acute antinociception in animals are similar to those in which observable behavioural effects occur, such as hypomotility and catatonia (Herzberg et al., 1997). In chronic pain conditions there is evidence of changes in the central nervous system, including up-regulation of CB-1 receptor expression (Siegling et al., 2001), that may result in antinociceptive efficacy with lower doses and hence there is an increasing interest in the role of cannabinoids in neuropathic pain (Bridges et al., 2001b; Pertwee, 1999; Rice et al., 2002; Vaughan and Christie, 2000). In addition, there is evidence emerging for antinociceptive efficacy of CB-2 agonists (Calignano et al., 1998; Ibrahim et al., 2003; Malan et al., 2001, 2002) in both inflammatory hyperalgesia, although this has not been consistently demonstrated (Bridges et al., 2001a; Hanus ˇ et al., 1999), and neuropathic pain (Ibrahim et al., 2003). The aim of this investigation was to determine the effect of the non-selective cannabinoid agonist CP55,940 on responses in neuropathic pain using a nerve-injury model and compare them with acute antinociceptive responses. In addition, the selective CB-1 cannabinoid antagonist SR141716A and the selective CB-2 cannabinoid antagonist SR144528 were administered with CP55, 950 in order to clarify the relative contribution of each receptor type to antinociception. Pain 109 (2004) 124–131 www.elsevier.com/locate/pain 0304-3959/$20.00 q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2004.01.020 * Corresponding author. Address: Department of Anaesthesia, St Vincent’s Hospital, P.O. Box 2900, 3065 Fitzroy, Vic., Australia. Tel.: þ 61-3-9288-2211; fax: þ61-3-9288-4193. E-mail address: david.scott@svhm.org.au (D.A. Scott).