Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro.
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.
['Slivicki|Richard A|RA|', 'Xu|Zhili|Z|', 'Mali|Sonali S|SS|', 'Hohmann|Andrea G|AG|']
D000581:Amidohydrolases D000700:Analgesics D000818:Animals D000970:Antineoplastic Agents D001549:Benzamides D048588:Benzoxazines D001921:Brain D002186:Cannabinoids D002219:Carbamates D045744:Cell Line, Tumor D002470:Cell Survival D004357:Drug Synergism D004361:Drug Tolerance D057809:HEK293 Cells D006801:Humans D006930:Hyperalgesia D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009025:Morpholines D009281:Naphthalenes D009437:Neuralgia D017239:Paclitaxel D019966:Substance-Related Disorders
Fatty-acid amide hydrolase Paclitaxel Cannabinoid 4T1 HeyA8 Chemotherapy-induced neuropathic pain Paclitaxel (PubChem CID: 436314) Rimonabant (PubChem CID: 104850) URB597 (PubChem CID: 1383884) URB937 (PubChem CID: 53394762) WIN55,212-2 (PubChem CID: 5311501)