Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

Abstract

Background As a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA. Methods To study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia. Results We created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3 g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice. Conclusions DORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal.

Gut Microbiota and Relevant Metabolites Analysis in Alcohol Dependent Mice

“…A photo beam-based tracking system was used to track the movement and calculate the time spent in each area. Anxiety-like effects were detected by increasing time spent in the dark compartment ( Alongkronrusmee et al, 2016 ).…”

Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies

“…Alcohol‐induced hyperalgesia can also be observed in mouse models (Alongkronrusmee et al, ; Bergeson et al, ; Smith et al, ), which allows for powerful genetic manipulations. For example, Alongkronrusmee and colleagues () recently reported that male wild‐type (WT) and δ‐opioid receptor (DOR) knockout C57BL/6 mice that were allowed to self‐administer alcohol (10%) versus water for 3 weeks in a 2‐bottle choice drinking‐in‐the‐dark (4 h/d) procedure exhibited escalation of alcohol intake to ~ 4 g/kg in 4 hours. A few days into alcohol abstinence, both groups exhibited mechanical hypersensitivity in the von Frey test, but this effect was exacerbated in DOR knockout mice.…”

Effect of Histone Deacetylase Inhibitor on Ethanol Withdrawal-Induced Hyperalgesia in Rats

“…Furthermore, deficits in brain-derived neurotrophic factor expression and dendritic spine density in amygdaloid circuits in response to chronic alcohol and withdrawal are also attenuated by trichostatin A (Pandey et al, 2008; You et al, 2014), which is mechanistically consistent with the role of this brain region in regulation of negative affect (Pandey et al, 2017). Pain represents another behavioral phenotype of negative affect, which develops during withdrawal (Edwards et al, 2012; Alongkronrusmee et al, 2016; Smith et al, 2016; Avegno et al, 2018; Kononoff et al, 2018) and can play a critical role in maintaining addictive behaviors (Egli et al, 2012; Apkarian et al, 2013). To the best of our knowledge, the effects of HDAC inhibitor treatment on ethanol withdrawal-induced hyperalgesia has not been investigated.…”