CB2 cannabinoid receptor mediation of antinociception

Abstract

Management of acute pain remains a significant clinical problem. In preclinical studies, CB2 cannabinoid receptor-selective agonists inhibit nociception without producing central nervous system side effects. The CB2 receptor-selective agonist AM1241 produces antinociceptive effects that are antagonized by CB2, but not CB1, receptor-selective antagonists, suggesting that activation of CB2 receptors results in antinociception. However, it has not been possible to definitively demonstrate that these effects are mediated by CB2 receptors, because we have lacked the pharmacological tools to confirm the in vivo receptor selectivity of the antagonists used. Further, recent evidence for cannabinoid-like receptors beyond CB1 and CB2 raises the possibility that AM1241 exerts its antinociceptive effects at uncharacterized CB2-like receptors that are also inhibited by AM630. The experiments reported here further test the hypothesis that CB2 receptor activation inhibits nociception. They evaluated the antinociceptive actions of AM1241 and the less-selective CB2 receptor agonist WIN55,212-2 in wild-type (CB2+/+) mice and in mice with genetic disruption of the CB2 receptor (CB2-/- mice). AM1241 inhibited thermal nociception in CB2+/+ mice, but had no effect in CB2-/- littermates. WIN55,212-2 produced equivalent antinociception in CB1+/+ and CB1-/- mice, while its antinociceptive effects were reduced in CB2-/- compared to CB2+/+ mice. The effects of morphine were not altered in CB2-/- compared to CB2+/+ mice. These data strongly suggest that AM1241 produces antinociception in vivo by activating CB2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB2 cannabinoid receptors for the treatment of acute pain.

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

“…CBr2 on keratinocytes mediates antinociception via opioid release. [17,18] CBr2 stimulates β-endorphin release from keratinocytes, leading to antinociception through μ-opioid receptors. We therefore investigated a CBr2 selective agonist in the mouse cancer pain model.…”

“…[24,40] In neuropathic pain, cannabinoids act at central and peripheral nerve CBr1s [20,34], and at CBr2s on keratinocytes. [18,20] Cannabinoid's analgesic action in cancer pain is less clear. [2,10,19] In a murine bone sarcoma pain model, systemic cannabinoids act through CBr1.…”

The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms

“…This observation is also consistent with earlier studies in which activation of CB 2 receptors produced both antinociception and antihyperalgesia in a variety of pain models. Peripheral or systemic administration of selective CB 2 receptor agonists produced antinociception to heat (Malan Jr. et al, 2001;Ibrahim et al, 2005;Ibrahim et al, 2006) and attenuated hyperalgesia produced by carrageenan (Nackley et al, 2003;Quartiho et al, 2003;Elmes et al, 2005;Gutierrez et al, 2007), capsaicin (Hohmann et al, 2004), and neuropathic injury . Peripheral injection of CB 2 receptor agonists also decreased mechanically-evoked responses of nociceptive spinal cord neurons following carrageenan-evoked inflammation and spinal nerve ligation (Elmes et al, 2004).…”

Crucial Role of CB2Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain

“…CB 2 receptors have been also proposed to be present in neurons (Van Sickle et al, 2005), although this issue is still controversial. CB 2 receptor activation induces analgesic effects in several animal models (Beltramo et al, 2006;Ibrahim et al, 2006;Bingham et al, 2007;Giblin et al, 2007), and selective CB 2 agonists could be potentially used as analgesic drugs, thus circumventing psychoactive side effects of CB 1 agonists .…”