Activation of
cannabinoid CB1 receptors suppresses pathological
pain but also produces unwanted side effects, including tolerance and physical dependence. Inhibition of
fatty-acid amide hydrolase (FAAH), the major
enzyme catalyzing the degradation of
anandamide (AEA), an
endocannabinoid, and other
fatty-acid amides, suppresses
pain without unwanted side effects typical of direct CB1 agonists. However, FAAH inhibitors have failed to show efficacy in several clinical trials suggesting that the right partnership of FAAH inhibition and pathology has yet to be identified. We compared efficacy of chronic treatments with a centrally penetrant FAAH inhibitor (
URB597), a peripherally restricted FAAH inhibitor (
URB937) and an orthosteric pan-
cannabinoid agonist (WIN55,212-2) in suppressing
neuropathic pain induced by the chemotherapeutic agent
paclitaxel. Each FAAH inhibitor suppressed the development of
paclitaxel-induced
neuropathic pain and reduced the maintenance of already established
allodynia with sustained efficacy. Tolerance developed to the anti-allodynic efficacy of WIN55,212-2, but not to that of
URB597 or
URB937, in each dosing paradigm. Challenge with the CB1 antagonist
rimonabant precipitated CB1-dependent withdrawal in
paclitaxel-treated mice receiving WIN55,212-2 but not
URB597 or
URB937. When dosing with either
URB597 or
URB937 was restricted to the development of neuropathy,
paclitaxel-induced
allodynia emerged following termination of
drug delivery. These observations suggest that both FAAH inhibitors were anti-allodynic rather than curative. Moreover, neither
URB597 nor
URB937 impeded the ability of
paclitaxel to reduce breast (4T1) or ovarian (HeyA8) tumor cell line viability. In fact,
URB597 and
URB937 alone reduced 4T1 tumor cell line viability, albeit with low potency, and the dose matrix of each combination with
paclitaxel was synergistic in reducing 4T1 and HeyA8 tumor cell line viability according to Bliss, Highest Single Agent (HSA) and Loewe additivity models. Both FAAH inhibitors synergized with
paclitaxel to reduce 4T1 and HeyA8 tumor cell line viability without reducing viability of non-
tumor HEK293 cells. Neither FAAH inhibitor reduced viability of non-
tumor HEK293 cells in either the presence or absence of
paclitaxel, suggesting that nonspecific cytotoxic effects were not produced by the same treatments. Our results suggest that FAAH inhibitors reduce
paclitaxel-induced
allodynia without the occurrence of CB1-dependence in vivo and may, in fact, enhance the anti-
tumor actions of
paclitaxel in vitro.