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

While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB1 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. Keywords: Pain, neuropathic, inflammatory, cannabinoid, fatty-acid amide hydrolase Introduction The psychoactive ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol (THC), is known to produce its physiological actions via an endogenous cannabinoid neurotransmitter system, specifically cannabinoid G-protein-coupled CB1 and CB2 receptors (Pertwee, 2005). There is now considerable evidence demonstrating that THC and a number of synthetic cannabinoid receptor agonists have analgesic activity in acute and chronic pain models. In particular, cannabinoid agonists reduce the allodynia (pain due to normally non-noxious stimuli) and hyperalgesia (increased pain sensitivity to normally noxious stimuli) associated with nerve injury-induced models of neuropathic pain (Herzberg et al., 1997; Bridges et al., 2001; Fox et al., 2001; Scott et al., 2004) and with inflammatory pain models (Smith et al., 1998; Hanus et al., 1999; Clayton et al., 2002; Kehl et al., 2003; De Vry et al., 2004). The antiallodynic, antihyperalgesic and anti-inflammatory actions of cannabinoid agonists in these chronic pain models are mediated via both cannabinoid CB1 and CB2 receptors (Hanus et al., 1999; Bridges et al., 2001; Fox et al., 2001; Clayton et al., 2002; Ibrahim et al., 2003; Kehl et al., 2003; De Vry et al., 2004). However, non-selective cannabinoid agonists produce a spectrum of motor and psychotropic side effects, which are mediated by central cannabinoid CB1 receptors (Compton et al., 1993; Herzberg et al., 1997; Fox et al., 2001; Malan et al., 2001; Scott et al., 2004). Like other neurotransmitter systems, the components of the cannabinoid signalling system also include endogenous cannabinoids (endocannabinoids), such as arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), as well as mechanisms for their synthesis, membrane transport and metabolism. The actions of endocannabinoids are terminated by removal from the extracellular space (anandamide via an anandamide membrane transporter), then subsequent enzymatic degradation (Hillard & Jarrahian, 2003; Lambert & Fowler, 2005). To date, two enzymes have been identified that metabolise endocannabinoids, namely fatty-acid amide hydrolase (FAAH) and monoglyceride lipase (MGL), which preferentially degrade anandamide and 2-AG, respectively (Sugiura et al., 1995; Cravatt et al., 1996; Goparaju et al., 1998; 1999; Beltramo & Piomelli, 2000; Dinh et al., 2002; Saario et al., 2004). It has been demonstrated that systemic application of anandamide produces analgesia in a number of acute and inflammatory pain models, albeit with reduced efficacy compared to synthetic cannabinoid receptor agonists (Devane et al., 1992; Fride & Mechoulam, 1993; Smith et al., 1994; Compton & Martin, 1997; Calignano et al., 1998; Jaggar et al., 1998; Richardson et al., 1998b). The reduced efficacy of systemically administered endocannabinoids is likely to be due to their rapid degradation, because metabolically stable anandamide analogues have increased analgesic efficacy and nonselective enzyme inhibitors enhance anandamide induced analgesia via cannabinoid CB1 receptor-dependent mechanisms (Compton & Martin, 1997; Adams et al., 1998). There is conflicting evidence as to whether endogenously released cannabinoids have a pain modulatory role. In support of this proposition, it has been demonstrated that painful stimuli increase anandamide release within pain modulatory brain structures (Walker et al., 1999). In addition, the selective cannabinoid CB1 receptor antagonist, SR141716 increases allodynia and hyperalgesia in inflammatory and neuropathic pain models, produces hyperalgesia in acute pain models and enhances pain responsiveness to the formalin test (Herzberg et al., 1997; Calignano et al., 1998; Richardson et al., 1998a; Strangman et al., 1998). In contrast, other studies have been unable to demonstrate an ‘endogenous cannabinoid tone' in these pain models (Beaulieu et al., 2000; Fox et al., 2001). The differences between these studies might be due to variations in stress levels and to a reduction in endogenous cannabinoid levels via metabolism. Thus, mice with a deletion of FAAH are hypoalgesic and display an increase in anandamide-induced analgesia (Cravatt et al., 2001; Lichtman et al., 2004b). Recently, a number of potent and selective FAAH inhibitors have been identified, including URB597, OL-53 and OL-135 (Boger et al., 2000; Kathuria et al., 2003; Lichtman et al., 2004a). In the present study, we examined the effects of the selective FAAH inhibitor, URB597, on allodynia and hyperalgesia in animal models of neuropathic and inflammatory pain.