Fatty acid amide hydrolase inhibition in the central nervous system 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 signaling activity of various lipid messengers involved in pain regulation, including agonists at cannabinoid receptors (e.g., anandamide) and peroxisome proliferator-activated receptor-α (PPAR-α) [e.g., palmitoylethanolamide (PEA)]. Here, we investigated whether pharmacological or genetic FAAH removal might prevent and/or reverse tolerance to the antinociceptive 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 (tail immersion test). The globally active FAAH inhibitor URB597 (1 and 3 mg/kg, intraperitoneal, i.p.) and 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 CB₁ cannabinoid receptor antagonist AM251 (3 mg/kg, i.p.), the CB₂ 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 liquid-chromatography/tandem mass spectrometry. Gene transcription was assessed by RT-qPCR.

KEY RESULTS:

URB597 prevented and reversed morphine tolerance in both male and female mice. The effect was mimicked by genetic FAAH deletion, but not by URB937. Antagonism of CB₂ , CB₁ or PPAR-α either suppressed (CB₂ ) or attenuated (CB₁ and PPAR-α) the effects of URB597. Anandamide mobilization was enhanced in the spinal cord of morphine-tolerant mice. Transcription levels of the anandamide-producing enzyme N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) and the PEA receptor PPAR-α were also elevated in spinal cord, whereas no changes were observed with CB₂ , CB₁ or FAAH.

CONCLUSION AND IMPLICATIONS:

The results support a role for central FAAH-regulated lipid signaling in the modulation of opiate tolerance, and point to FAAH as a potential target for opiate-sparing medications.

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