CB ₂ cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids

Abstract

CB2 cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB2 receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB2 receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB2 receptormediated inhibition of pain responses. Here, we test the hypothesis that CB2 receptor activation stimulates release from keratinocytes of the endogenous opioid ␤-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB2 receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to ␤-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that ␤-endorphin is necessary for CB2 receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in -opioid receptordeficient mice. Hindpaw injection of ␤-endorphin was sufficient to produce antinociception. AM1241 stimulated ␤-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB2 cannabinoid receptorselective antagonist and was not observed in skin from CB2 cannabinoid receptor-deficient mice. These data suggest that CB2 receptor activation stimulates release from keratinocytes of ␤-endorphin, which acts at local neuronal -opioid receptors to inhibit nociception. Supporting this possibility, CB2 immunolabeling was detected on ␤-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of ␤-endorphin, where CB2 receptors are present, leading to anatomical specificity of opioid effects.␤-endorphin ͉ nociception ͉ pain ͉ keratinocyte ͉ skin C B 2 cannabinoid receptor-selective agonists are very promising candidates for the treatment of pain. Activation of CB 2 cannabinoid receptors inhibits nociception to thermal and mechanical stimuli (1, 2), thermal and tactile hypersensitivity produced by peripheral inflammation (2-4), and tactile and thermal hypersensitivity produced in a neuropathic pain model (5). Experimental findings suggesting that activation of peripheral (noncentral nervous system) CB 2 receptors is necessary and sufficient to inhibit pain responses come from site-specific injections of CB 2 receptor-selective agonists and antagonists (1, 3, 4). Importantly, CB 2 cannabinoid receptor-selective agonists do not cause central nervous system (CNS) effects (1, 6), consistent with the inability to demonstrate the expression of CB 2 receptors in the normal CNS (7-10). The lack of CNS effects is an important feature of this class of drug candidates because the efficacy of current pain therapies is frequently limited by CNS side effects. However, enthusiasm for this therapeutic approach has been tempered by the lack of information regarding the mechanism underlying the inhibition of n...

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.…”

Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes

“…Therefore one of them, HU-308 [102], does not produce hypothermia, catalepsy, or behavioural changes, while the role of CB 2 receptors is fundamental in other cannabimimetic actions, such as immunomodulatory and antiproliferative effects. On the other hand, as mentioned earlier, new CB 2 receptor properties are being discovered, as it has been confirmed that they indirectly stimulate opioid receptors located in primary afferent pathways [67].…”

“…Structurally they consist of seven folded transmembrane helices with intra-and extracellular loops, functionally involved in signal transduction. The CB 2 receptor is located mainly in the immune system, but has been found in others sites, as in keratinocytes [67]. On the other hand, the CB 1 receptor, which is the cannabinoid receptor that has been most studied, has high levels in brain but also lower levels in spinal and peripheral nervous tissue (including areas important for pain perception, as will be discussed below).…”

“…Furthermore, CB 2 receptors have novel pain control actions. A CB 2 -mediated effect exists, consisting in the indirect stimulation of opioid receptors located in primary afferent pathways [67], as will be described in more detail in the next section. Thus, cannabinoid compounds can modulate hyperalgesia of various origins and they are effective even in inflammatory and neuropathic pain [10,133], which are conditions often refractory to treatment.…”

“…These CB 2 receptors, when activated, stimulate release of the endogenous opioid -endorphin, which then acts at -opioid receptors on local primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB 2 receptorselective agonist AM1241 were prevented in rats when naloxone or antiserum to -endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, or was not observed in skin from CB 2 cannabinoid receptordeficient mice and -opioid receptor-deficient mice, suggesting that -endorphin is necessary for CB 2 receptor-mediated antinociception [67].…”