Combined inhibition of FMH and COX produces enhanced .anti-allodynic effects in mouse neuropathic and iniammatory pain models

摘要

Common pharmacological treatments of neuropathic and chronic inflammatory pain conditions generally lack efficacy and/or are associated with significant untoward side effects. However, recent predinical data indicate that combined inhibition of cyclooxygenase (COX) and fatty acid amide hydrolase (FMH), the primary catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA), produces enhanced antinodceptive effects in a variety of murine models of pain. Accordingly, the primary objective of the present study was to investigate the consequences of co-administration of the COX inhibitor diclofenac and the highly selective FMH inhibitor PF-3845 in models of neuropathic pain (i.e, chronic constrictive injury of the sciatic nerve (CO)) and inflammatory pain induced by an intraplantar injection of carrageenan. Here, we report that combined administration of subthreshold doses of these drugs produced enhanced antinociceptive effects in CCI and carrageenan pain models, the latter of which was demonstrated to require both CB_1 and CB_2 receptors. The combined administration of subthreshold doses of these drugs also increased AEA levels and decreased prostaglandin levels in whole brain. Together, these data add to the growing research that dual blockade of FMH and COX represents a potential therapeutic strategy for the treatment of neuropathic and inflammatory pain states.