Intricate involvement of delta opioid receptors in alcohol withdrawal induced hyperalgesia

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Van Rijn RM1, Alongkronrusmee D1
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States
Chronic pain and hyperalgesia are a major health issue for which adequate treatment options are still lacking. Withdrawal from long-term alcohol consumption can induce anxiety and hyperalgesia in both humans and rodents. These withdrawal signs can contribute to relapse and perpetuate alcohol abuse. The molecular mechanisms underlying alcohol withdrawal hyperalgesia are not well understood, which stifles development of new therapeutics. Interestingly, delta opioid receptors are heavily expressed in mechano-sensitive neurons. Moreover, stress, chronic inflammation and alcohol exposure have been reported to upregulate delta opioid receptors in these neurons. As such delta opioid receptors are an interesting target for chronic pain conditions involving mechanical allodynia and hyperalgesia. We hypothesize that delta opioid receptors play a protective role in alcohol-withdrawal induced mechanical allodynia (AWiMA) and that delta opioid receptor agonists could reduce AWiMA. To establish AWiMA, wild-type and delta opioid receptor knockout C57BL/6 mice were exposed to alcohol either in a limited access 2-bottle choice drink in the dark paradigm or by oral gavage (3 g/kg alcohol) for three weeks followed by a period of abstinence. Alcohol withdrawal was evident from increased anxiety-like behaviors in mice. Importantly, AWiMA, as measured by Von Frey filaments, was observed within a couple of days and severity and duration of AWiMA was enhanced in delta opioid receptor knockout mice compared to wild type mice. A delta opioid receptor selective agonist TAN-67 was able to reduce AWiMA in both animal models, but with reduced potency in mice exposed to alcohol by oral gavage. Similar to delta opioid receptor knockout, blockade of delta opioid receptors with the delta opioid receptor selective antagonist naltrindole (2 mg/kg, s.c.) produced a hyperalgesic state. From our current results it is evident that delta opioid receptors play a protective role against AWiMA, however more studies are needed to understand the temporal aspect and precise mechanism of this delta opioid receptor mediated analgesia.