Inhibition of Fatty Acid Amide Hydrolase: A Potential Treatment for Neuropathic Pain

There are limited treatment options for neuropathic pain, a debilitating condition characterized by pain hypersensitivity. There is, however, growing interest in cannabinoids because CB1- and CB2-receptor agonists are analgesic in acute and chronic pain, and increases in endogenous cannabinoids are

There are limited treatment options for neuropathic pain, a debilitating condition characterized by pain hypersensitivity. There is, however, growing interest in cannabinoids because CB 1 -and CB 2receptor agonists are analgesic in acute and chronic pain, and increases in endogenous cannabinoids are effective in animal models of neuropathic pain (Bridges et al., 2001;Jayamanne et al., 2006).
A recent study in The Journal of Neuroscience by Jhaveri et al. (2006) investigated whether inhibition of fatty acid amide hydrolase (FAAH) alters responses of dorsal horn neurons in neuropathic pain (Fig. 1). FAAH is the enzyme responsible for metabolism of the endocannabinoid anandamide. Jhaveri et al. (2006) report a marked reduction in paw-withdrawal threshold, indicative of mechanical allodynia in spinal nerve-ligated (SNL), but not in sham-operated rats. Increasing weights of monofilaments applied to the hindpaw of SNL or sham-operated rats evoked an incremental increase in neuronal firing in wide dynamic-range spinal dorsal horn neurons in vivo [Jhaveri et al. (2006), their Fig. 1 (http://www.jneurosci. org/cgi/content/full/26/51/13318/F1)]. The firing frequency, however, was lower in the SNL group regardless of whether the stimulus intensity was innocuous or noxious consistent with a reduction in "peripheral drive" and an overall decrease in spinal neuronal excitability after peripheral nerve injury (Chapman et al., 1998).
Intraplantar injection of URB597, an FAAH inhibitor, suppressed the mechanically evoked responses of wide dynamicrange spinal neurons in sham-operated rats [Jhaveri et al. (2006) . The latter finding suggests this effect may involve peripheral endocannabinoids. In contrast, a fourfold higher dose of intraplantar URB597 was required to inhibit neuronal responses in SNL rats [Jhaveri et al. (2006), their Fig.  2 B, (http://www.jneurosci.org/cgi/ content/full/26/51/13318/F2)], and did not coincide with an increase in peripheral endocannabinoids. Jhaveri et al. (2006) attributed this result to increased FAAH activity and to changes in pH in the hindpaw of neuropathic rats, which would attenuate the potency of the drug. The authors also suggest that peripheral levels of endocannabinoids in SNL rats could have been affected by alternate met-abolic pathways, such as the cyclooxygenase pathway. However, in addition to these possibilities, endocannabinoid levels could have been influenced by activity of the lipoxygenase pathway or by endocannabinoid carrier-mediate reuptake.
In previous studies, these authors reported that activation of peripheral CB 2 -receptors produces a strikingly similar reduction in mechanically evoked response of spinal neurons in SNL and sham-operated rats (Elmes et al., 2004). Others have also shown that CB 2receptors are upregulated on sensory afferent terminals in the lumbar spinal cord of nerve-injured animals (Wotherspoon et al., 2005) and agonists of CB 2 -receptors suppress pain hypersensitivity associated with neuropathic pain (Beltramo et al., 2006). In light of the evidence for involvement of CB 2 -receptors in neuropathic pain, some of the effects resulting from URB597 treatment could involve CB 2 -receptors.
A key issue that remains to be ad-dressed is whether inhibition of neuronal responses and augmentation of endocannabinoid levels by URB597 corresponds to a behavioral reduction in mechanical allodynia in SNL rats. This issue is important because FAAHϪ/Ϫ knock-out mice develop pain hypersensitivity after peripheral nerve injury, despite possessing 15-fold higher brain anandamide levels than wild-type controls (Lichtman et al., 2004). In addition, URB597 had no effect on mechanical allodynia in a partial sciatic nerve ligation model of neuropathic pain (Jayamanne et al., 2006), and there are concerns regarding the specificity of the drug (Zhang et al., 2007). Thus, a behavioral correlate to the neuronal effects of URB597 would strengthen the proposed link between FAAH inhibitors and the treatment of neuropathic pain.

Figure 1.
A schematic representation of the spinal and peripheral endocannabinoid system. The effects of anandamide (AEA) and 2-arachidonyl glycerol (2-AG) are mediated through activation of cannabinoid CB 1 -and CB 2 -receptors. AEA is internalized by a putative carrier-mediated transporter and metabolized by FAAH to produce arachidonic acid and ethanolamine. Although 2-AG activity is principally metabolized by monoacylglycerol lipase, termination of 2-AG activity can also occur through FAAH. Pharmacological inhibition of FAAH results in elevated endocannabinoid levels and a consequent reduction in spinal pain transmission.