PT  - JOURNAL ARTICLE
AU  - Richard A Slivicki
AU  - Shahin A Saberi
AU  - Vishakh Iyer
AU  - Kiran Vemuri
AU  - Alexandros Makriyannis
AU  - Andrea G Hohmann
TI  - Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase synergize with the opioid analgesic morphine to suppress chemotherapy-induced neuropathic nociception without enhancing effects of morphine on gastrointestinal transit
AID  - 10.1124/jpet.118.252288
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.252288
4099  - http://jpet.aspetjournals.org/content/early/2018/10/10/jpet.118.252288.short
4100  - http://jpet.aspetjournals.org/content/early/2018/10/10/jpet.118.252288.full
AB  - Opioid-based therapies remain a mainstay for chronic pain management, but unwanted side-effects limit therapeutic use. We compared efficacies of brain permeant and impermeant inhibitors of fatty-acid amide hydrolase (FAAH) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Paclitaxel produced mechanical and cold allodynia without altering nestlet shredding or marble burying behaviors. We compared FAAH inhibitors that differ in their ability to penetrate the central nervous system for anti-allodynic efficacy, pharmacological specificity and synergism with the opioid analgesic morphine. URB597, a brain permeant FAAH inhibitor, attenuated paclitaxel-induced allodynia via CB1 and CB2 mechanisms. URB937, a brain impermeant FAAH inhibitor, suppressed paclitaxel-induced allodynia through a CB1 mechanism only. AM6545, a peripherally-restricted CB1 antagonist, fully reversed the anti-allodynic efficacy of URB937 but only partially reversed that of URB597. Thus, URB937 suppressed paclitaxel-induced allodynia through a mechanism that was dependent upon peripheral CB1 receptor activation only. Anti-allodynic effects of both FAAH inhibitors were reversed by AM251. Anti-allodynic effects of URB597 but not URB937 were reversed by AM630. Isobolographic analysis revealed synergistic interactions between morphine and either URB597 or URB937 in reducing paclitaxel-induced allodynia. A leftward shift in the dose-response curve of morphine was observed when morphine was co-administered with either URB597 or URB937, consistent with morphine sparing. However, neither URB937 nor URB597 enhanced morphine-induced deficits in colonic transit. Thus, our findings suggest that FAAH inhibition may represent a therapeutic avenue to reduce the overall amount of opioid needed for treating neuropathic pain with potential to reduce unwanted side-effects that accompany opioid administration.