Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model

• The dual FAAH/MAGL inhibitor JZL195 was examined in an inflammatory pain model.
• Unlike a CB agonist, JZL195 reduced allodynia below side-effect inducing doses.
• Both CB2 and CB2 receptors contributed to the JZL195 anti-allodynia.
• Both FAAH and MAGL contributed additively to the JZL195 anti-allodynia.
• JZL195 has potential as an analgesic in inflammation induced pain.

The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.