Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice.

Background And Purpose: Fatty acid amide hydrolase (FAAH) is an intracellular serine amidase that terminates the signalling of various lipid messengers involved in pain regulation, including anandamide and palmitoylethanolamide. Here, we investigated the effects of pharmacological or genetic FAAH removal on tolerance to the anti-nociceptive effects of morphine.

Experimental Approach: We induced tolerance in male and female mice by administering twice-daily morphine for 7 days while monitoring nociceptive thresholds by the tail immersion test. The globally active FAAH inhibitor URB597 (1 and 3 mg·kg , i.p.) or the peripherally restricted FAAH inhibitor URB937 (3 mg·kg , i.p.) were administered daily 30 min prior to morphine, alone or in combination with the cannabinoid CB receptor antagonist AM251 (3 mg·kg , i.p.), the CB receptor antagonist AM630 (3 mg·kg , i.p.), or the PPAR-α antagonist GW6471 (4 mg·kg , i.p.). Spinal levels of FAAH-regulated lipids were quantified by LC/MS-MS. Gene transcription was assessed by RT-qPCR.

Key Results: URB597 prevented and reversed morphine tolerance in both male and female mice. This effect was mimicked by genetic FAAH deletion, but not by URB937. Treatment with AM630 suppressed, whereas treatment with AM251 or GW6471, attenuated the effects of URB597. Anandamide mobilization was enhanced in the spinal cord of morphine-tolerant mice. mRNA levels of the anandamide-producing enzyme N-acyl-phosphatidylethanolamine PLD (NAPE-PLD) and the palmitoylethanolamide receptor PPAR-α, but not those for CB , CB receptors or FAAH, were elevated in spinal cord CONCLUSION AND IMPLICATIONS: FAAH-regulated lipid signalling in the CNS modulated opiate tolerance, suggesting FAAH as a potential target for opiate-sparing medications.