Pain
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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 CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R). 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 CB(1)R or CB(2)R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of α,β-amyrin. ⋯ 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.
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Nucleotides contribute to the sensation of acute and chronic pain, but it remained enigmatic which G protein-coupled nucleotide (P2Y) receptors and associated signaling cascades are involved. To resolve this issue, nucleotides were applied to dorsal root ganglion neurons under current- and voltage-clamp. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uridine triphosphate (UTP), but not uridine diphosphate (UDP), depolarized the neurons and enhanced action potential firing in response to current injections. ⋯ The facilitation of TRPV(1), but not the inhibition K(V)7 channels, was prevented by a protein kinase C inhibitor. Simultaneous blockage of K(V)7 channels and of TRPV(1) channels prevented nucleotide-induced membrane depolarization and action potential firing. Thus, P2Y(1) and P2Y(2) receptors mediate an excitation of dorsal root ganglion neurons by nucleotides through the inhibition of K(V)7 channels and the facilitation of TRPV(1) channels via a common bifurcated signaling pathway relying on an increase in intracellular Ca(2+) and an activation of protein kinase C, respectively.
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Editorial Comment
A decade of effects on sickleave after multidisciplinary rehabilitation?