Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models

Abstract

While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB(1) receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210 in rat models of chronic inflammatory and neuropathic pain. Systemic administration of URB597 (0.3 mg kg(-1)) and HU210 (0.03 mg kg(-1)) both reduced the mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. In contrast, HU210, but not URB597, reduced mechanical allodynia in the partial sciatic nerve-ligation model of neuropathic pain. HU210, but not URB597, produced a reduction in motor performance in unoperated rats. The effects of URB597 in the CFA model were dose dependent and were reduced by coadministration with the cannabinoid CB1 antagonist AM251 (1 mg kg(-1)), or the CB2 and SR144528 (1 mg kg(-1)). Coadministration with AM251 plus SR144528 completely reversed the effects of URB597. These findings suggest that the FAAH inhibitor URB597 produces cannabinoid CB1 and CB2 receptor-mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation.

Figures

Figure 1

URB597 reduces allodynia in an inflammatory, but not a neuropathic pain model. Time plots of the effect of URB597 (0.3 mg kg−1, filled circles), HU210 (0.03 mg kg−1, filled squares) or vehicle alone (open circles) on (a) mechanical paw withdrawal threshold (PWT) in nerve-injured animals, (b) mechanical PWT in complete Freund's adjuvant (CFA)-injected animals and (c) thermal paw withdrawal latency (PWL) in CFA-injected animals. Animals received an intraperitoneal injection of URB597, HU210 or a matched vehicle at time 0 h (a) 14 days after partial ligation of the sciatic nerve (post-PNL), or (b, c) 24 h after CFA injection (post-CFA) into the plantar surface of the hindpaw. The mechanical PWT and thermal PWT are also shown prior to nerve injury (Pre-PNL) and CFA injection (Pre-CFA). Data are shown as the mean±s.e.m. *Denotes P<0.05 compared to time 0 post-PNL, or post-CFA.

Figure 2

The effect of URB597 is dose dependent. Bar charts depicting the mean effect of intraperitoneal injection of cannabinoids on (a) mechanical paw withdrawal threshold (PWT) and (b) thermal paw withdrawal latency (PWL) in animals 24 h after CFA injection (post-CFA) into the plantar surface of the hindpaw. The mean effect of URB597 (0.03–0.3 mg kg−1), HU210 (0.03 mg kg−1) and vehicle were calculated as the area under the curve (AUC) postinjection compared to the preinjection baseline value. Data are shown as the mean±s.e.m. *Denotes P<0.05, compared to vehicle.

Figure 3

The effect of URB597 is mediated by cannabinoid CB1 and CB2 receptors. Bar charts depicting the mean effect of intraperitoneal injection of cannabinoids on (a) mechanical paw withdrawal threshold (PWT) and (b) thermal paw withdrawal latency (PWL) in animals 24 h after CFA injection (post-CFA) into the plantar surface of the hindpaw. The mean effects of URB597 (0.3 mg kg−1) alone; in combination with the cannabinoid CB1 receptor antagonist AM251 (1.0 mg kg−1) and/or the cannabinoid CB2 receptor antagonist SR144528 (1.0 mg kg−1); AM251 and SR144528 alone; and vehicle were calculated as the area under the curve (AUC) postinjection compared to the preinjection baseline value. Data are shown as the mean±s.e.m. #P<0.001, compared to vehicle. *P<0.05, **P<0.01, ***P<0.001, compared to URB597 alone.

Figure 4

URB597 does not affect motor performance. (a) Time plots of rotarod latency following intraperitoneal injection of URB597 (0.3 mg kg−1), HU210 (0.03 mg kg−1) or vehicle at time 0 h. These animals had not undergone prior PNL surgery, or CFA injection. (b) Bar chart depicting the mean effect of intraperitoneal injection of cannabinoids on rotarod latency, calculated as the area under the curve (AUC) postinjection compared to the preinjection baseline value. Data are shown as the mean±s.e.m. *Denotes P<0.05, compared to time 0 post-PNL, or post-CFA in (a) and compared to vehicle in (b).