Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release

Abstract

Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gβγ subunits from Gi/o, but not Gαs, were involved in CB2 receptor activation-induced β-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced β-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca(2+). Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced β-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced β-endorphin release through Gi/o-Gβγ-MAPK-Ca(2+) signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.

Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal

“…Other putative CB2 agonists suggested to exhibit antiallodynic effects in CFA model are GW405833 (Li et al, 2017), AM1241 (Hsieh et al, 2011;Gao et al, 2016), A836339 (Yao et al, 2009;Hsieh et al, 2011), GW842166X (Giblin et al, 2007), and A-796260 (Yao et al, 2008); however, most studies have not thoroughly evaluated pharmacologic specificity in vivo. Strikingly, in our previously published work, the putative CB2 agonist GW405833, which did not produce cardinal signs of CB1 activation in the tetrad, suppressed mechanical allodynia in both CFA and PSNL model in mice, but these effects were mediated by CB1 and not CB2 mechanisms (Li et al, 2017).…”

Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics

“…CB2 activation by cannabinoid and non-cannabinoid cannabis compounds, such as β-caryophyllene and tetracyclic triterpene euphol, leads to the local release of analgesic compounds such as the endogenous opioid β-endorphin from keratinocytes 70,71. Furthermore, various anti-inflammatory autacoids from the families of N-acylethanolamines, resolvins, protectins, and maresins may contribute to restoring homeostasis and anti-nociceptive activity.…”

Peripheral Mechanisms of Neuropathic Pain—The Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain

“…The keratinocytes may express the modulatory analgesic properties as well. For instance, CB2 activation by cannabinoid and noncannabinoid cannabis compounds, such as β-caryophyllene and tetracyclic triterpene euphol, leads to the local release of endogenous opioid β-endorphin from keratinocytes [98][99][100]. The data from clinical and preclinical data confirm the role of keratinocytes in nociception, either in transduction or peripheral modulation of nociceptive input.…”

“…In the periphery, CB1 receptors are expressed on nociceptive nerve endings and the DRG, whereas CB2 receptors are located in immune cells and keratinocytes [78,172]. Either CB1 or CB2 receptors may be targeted by cannabinoids administered topically, evoking analgesic effect in both inflammatory and neuropathic pain [78,81,[98][99][100]172].…”