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The pentacyclic triterpene α,β-amyrin binds to CB1 and CB2 receptors and reduces inflammation and hyperalgesia in 2 models of persistent pain in mice.In this study, we report that α,β-amyrin, a plant-derived pentacyclic triterpene, reduced persistent inflammatory and neuropathic hyperalgesia in mice by a direct activation of the CB1 and CB2 cannabinoid receptors (CB1R and CB2R). The oral treatment with α,β-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 CB1R or CB2R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of α,β-amyrin. Of note, binding studies showed that α,β-amyrin directly bound with very high affinity to CB1R (Ki = 0.133 nM) and with a lower affinity to CB2R (Ki = 1989 nM). Interestingly, α,β-amyrin, ACEA (CB1R agonist), or JWH-133 (CB2R agonist), at doses that caused antinociception, failed to provoke any behavioral disturbance, as measured in the tetrad assay. In addition, α,β-amyrin largely decreased interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), keratinocyte-derived chemokine (KC) and interleukin 6 (IL-6) levels, and myeloperoxidase activity. Likewise, α,β-amyrin prevented the activation of the transcriptional factors: nuclear factor κB (NF-κB) 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 α,β-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-κB, CREB and cyclooxygenase 2.