Abstract
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.
Highlights
Opioids are essential drugs for pain management, long-term use is accompanied by tolerance, necessitating dose escalation, and dependence
We explored the ability of AM11095 to modulate morphine’s effects on the response of locus coeruleus (LC) noradrenergic (NA) neurons to noxious stimuli, a neural correlate of its antinociceptive effects, and on the tolerance that develops after chronic morphine administrations
We report that the N-acylethanolamine acid amidase (NAAA) inhibitor AM11095 enhanced morphine-induced antinociception, delayed tolerance development, and reduced chronic morphineinduced glial activation in the spinal cord
Summary
Opioids are essential drugs for pain management, long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. One of the major problems of opioid use is the development of tolerance to the analgesic effect, leading to dosage increases and to the exacerbation of drug side effects, such as constipation, addiction, and respiratory depression, which undergo different degrees of tolerance. The mechanisms that underlie the development of opioid tolerance are diverse and extensively studied and involve receptor desensitization, phosphorylation, uncoupling. It is imperative to investigate pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain). N-acylethanolamines (NAEs), endocannabinoid-like lipid neuromodulators such as palmitoylethanolamide (PEA), show promise in treating inflammation and pain. Among NAEs, the most studied in the context of pain is PEA. Tissue levels of PEA are increased in brain areas involved in nociception and in the spinal cord following neuropathic pain induction and in human conditions associated with pain [11, 12]
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