Antinociceptive effects of the non-selective cannabinoid receptor agonist CP 55,940 are absent in CB1−/− and not CB2−/− mice in models of acute and persistent pain
Introduction
Cannabinoid receptor agonists have been shown to be effective in animal models of pain by inhibiting acute nociceptive responses, as well as reversing the behavioral hypersensitivity that occurs from chemical stimuli, peripheral inflammation, or neuropathy (for review, see Pertwee, 2001, Whiteside et al., 2007). While cannabinoid receptor agonists have been shown to produce antinociception in a variety of animal pain models, efficacy is typically associated with significant side effects, including catalepsy, motor deficits, and hypothermia (Herzberg et al., 1997, Ledent et al., 1999, Romero et al., 2002, Smith et al., 1994). It has been suggested that these adverse effects, in addition to the antinociceptive efficacy of cannabinoid receptor agonists, occur as a consequence of CB1 receptor activation in the central nervous system (CNS) (Ledent et al., 1999, Lichtman and Martin, 1997, Martin et al., 1993, Martin et al., 1999, Richardson et al., 1998; ; Zimmer et al., 1999).
In contrast to CB1 receptors, CB2 receptors are found primarily in peripheral immune cells (Facci et al., 1995, Galiegue et al., 1995, Rice et al., 2002), and several reports have demonstrated antinociceptive efficacy of selective CB2 receptor agonists in models of acute, inflammatory and neuropathic pain (Bridges et al., 2001, Elmes et al., 2005, Ibrahim et al., 2003, Quartilho et al., 2003, Scott et al., 2004, Valenzano et al., 2005). Results from studies such as these have suggested that selective CB2 receptor agonists may produce antinociception without exhibiting significant side effects, and support the potential development of selective CB2 receptor agonists as a viable alternative to non-selective cannabinoid agonists for the treatment of pain.
Since reports in the literature support a role for both CB1 and CB2 receptors in antinociception, non-selective cannabinoid receptor agonists may be used as a tool to investigate the contribution of each cannabinoid receptor subtype to antinociceptive efficacy. Commonly used non-selective cannabinoid receptor agonists include CP 55,940 and WIN 55,212-2. CP 55,940 displays similar affinity for both CB1 and CB2 receptors (Felder et al., 1995), and several studies have described the antinociceptive action of CP 55,940 in rat pain models (Fox et al., 2001, Lichtman and Martin, 1997, Romero et al., 2002, Scott et al., 2004). One utility of mouse pain models is that antinociceptive mechanisms of action may be investigated using transgenic or knockout mice. In the present study, we examined the antinociceptive effects of CP 55,940 in acute and persistent pain models in C57BL/6 mice, and also determined effects on motor coordination. Additionally, to investigate the cannabinoid receptor subtypes involved in mediating antinociception, the effects of CP 55,940 were evaluated in CB1 receptor knockout (CB1−/−), CB2 receptor knockout (CB2−/−), and wild type littermate control mice (CB1+/+, CB2+/+).
Section snippets
Animals
Mice were maintained in a climate-controlled room on a 12:12 h light/dark cycle with free access to food and water. All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Merck & Co., Inc., West Point, PA and were in accordance with The Guide for the Care and Use of Laboratory Animals. C57BL/6 mice were obtained from Taconic Farms (Germantown, NY). Breeding pairs of mice heterozygous for the CB1 receptor gene (CB1+/−) were obtained from Andreas Zimmer
Behavioral phenotype of C57BL/6, CB1+/+, CB2+/+, CB1−/−, and CB2−/− mice in models of nociception and motor coordination
Behavioral phentotyping of all mice was performed by determining: a) baseline sensitivity to von Frey filament stimulation, b) tactile allodynia following CFA injection, c) tactile allodynia following SNL, d) sensitivity to warm water tail immersion, and e) motor coordination on the rotarod. As summarized in Table 1, the phenotypes of control C57BL/6, CB1+/+, CB2+/+, CB1−/−, and CB2−/− mice were similar in all tests of nociception. In terms of motor coordination, all groups of mice were similar
Discussion
The results from the present study suggest that the antinociceptive effects and impaired motor coordination following administration of the non-selective cannabinoid receptor agonist CP 55,940 in mice are mediated by CB1, and likely not CB2 receptors. CP 55,940 is a cannabinoid receptor agonist that has been shown to have similar binding affinity (CB1 Ki = 3.7 nM; CB2 Ki = 2.5 nM) and potency (CB1 cAMP IC50 = 1.8 nM; CB2 cAMP IC50 = 2.9 nM) for CB1 and CB2 receptors in stably transfected cell
Acknowledgements
We would like to thank the Laboratory Animal Resources Department at Merck Research Laboratories West Point for providing surgical support for the SNL model.
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