Activation of cannabinoid receptors by the pentacyclic triterpene alpha,beta-amyrin inhibits inflammatory and neuropathic persistent pain in mice.

摘要

In this study, we report that alpha,beta-amyrin, a plant-derived pentacyclic triterpene, reduced persistent inflammatory and neuropathic hyperalgesia in mice by a direct activation of the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R). The oral treatment with alpha,beta-amyrin (30 mg/kg) significantly reduced mechanical and thermal hyperalgesia and inflammation induced by complete Freund's adjuvant (CFA) and by partial sciatic nerve ligation (PSNL). The pretreatment with either CB(1)R or CB(2)R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of alpha,beta-amyrin. Of note, binding studies showed that alpha,beta-amyrin directly bound with very high affinity to CB(1)R (K(i)=0.133 nM) and with a lower affinity to CB(2)R (K(i)=1989 nM). Interestingly, alpha,beta-amyrin, ACEA (CB(1)R agonist), or JWH-133 (CB(2)R agonist), at doses that caused antinociception, failed to provoke any behavioral disturbance, as measured in the tetrad assay. In addition, alpha,beta-amyrin largely decreased interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), keratinocyte-derived chemokine (KC) and interleukin 6 (IL-6) levels, and myeloperoxidase activity. Likewise, alpha,beta-amyrin prevented the activation of the transcriptional factors: nuclear factor kappaB (NF-kappaB) and cyclic adenosine monophosphate response element binding (CREB) and the expression of cyclooxygenase 2 in mice footpads and spinal cords. The present results demonstrated that alpha,beta-amyrin exhibits long-lasting antinociceptive and anti-inflammatory properties in 2 models of persistent nociception via activation of cannabinoid receptors and by inhibiting the production of cytokines and expression of NF-kappaB, CREB and cyclooxygenase 2.