Fatty Acid Amide Hydrolase (FAAH) Inhibitors Exert Pharmacological Effects, but Lack Antinociceptive Efficacy in Rats with Neuropathic Spinal Cord Injury Pain

Abstract

Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.

Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy

“…FAAH inhibitors have been reported to reduce pain behaviors in several animal models in the absence of cannabinoid-like untoward side effects (Ahn et al, 2009, 2011; Chang et al, 2006; Guindon et al, 2013; Jayamanne et al, 2006; Jhaveri et al, 2006; Kinsey et al, 2009; Russo et al, 2007). Although CNS levels of FAAs were not assayed in the current study, recent findings in our laboratory showed consistent elevations of FAAs, including AEA, in both brain and spinal cord at the doses and time courses of URB597 and PF-3485 in the current study (Hama et al, 2014). …”

“…URB597 is selective covalent inhibitor of FAAH that elevates AEA and other FAAs in brain and spinal cord after systemic administration in rodents and primates (Ahn et al, 2009; Hama et al, 2014; Justinova et al, 2008; Kinsey et al, 2009; Russo et al, 2007). It has antihyperalgesic effects in various rodent pain models (Ahn et al, 2008; Guindon et al, 2013; Jahaveri et al, 2006; Jayamanne et al, 2006; Kinsey et al, 2009; Naidu et al, 2010; Russo et al, 2007).…”

“…were used for comparison and approximation of anti-nociceptive potency of the FAAH inhibitors. Since the goal of this study was to evaluate the maximum potential benefit of the FAAH inhibitors, and these agents reach a plateau in their ability to increase CNS levels of endocannabinoids, the dose producing maximum AEA elevations in previous studies in our lab and others was tested (10 mg/kg of PF-3845 and 3 mg/kg of URB597; Ahn et al, 2009; Bradshaw et al, 2009; Hama et al, 2014). In addition, both a higher and lower dose of both of these FAAH inhibitors (1 and 10 mg/kg URB597; 3 and 20 mg PF-3845) were included to determine for dose-ranging.…”

Cannabinoids to treat spinal cord injury

“…NAPE-PLD in the dorsal horn may be associated with dendrites, astrocytes and microglia (Hegyi et al, 2012). Other N-acyl ethanolamines (oleoylethanolamine, palmitoylethanolamine) that share the same enzymatic machinery with anandamide, are also produced in the normal cord and are modulated after SCI (Garcia-Ovejero et al, 2009;Hama et al, 2014), but they lack affinity for cannabinoid receptors.…”

Neuroprotective effects of the Buyang Huanwu decoction on functional recovery in rats following spinal cord injury

“…15 After routine disinfection, a surgical incision was made through the skin, subcutaneous tissue, and the T8-T12 vertebral laminae to expose the spinal canal ( Fig. 2A).…”