Opioids are
essential drugs for
pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance
opioid analgesic effects and/or attenuate the development of tolerance (with a desirable
opioid-sparing effect in treating
pain) are actively sought. Among them, N-
palmitoylethanolamide (PEA), an endogenous
lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of
morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting
N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing
enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates
morphine's antinociceptive effects and attenuates the development of
morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from
pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3-30 mg/kg) enhanced the antinociceptive effects of
morphine and delayed the development of tolerance to chronic
morphine in behaving rats. Consistently, AM11095 enhanced
morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of
morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic
morphine were paralleled by a decrease in glial activation in the spinal cord, an index of
opioid-induced
neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the
analgesic effects of
opioids and delay the development of tolerance.