Role of opioid tapering in rescuing anxiety and social novelty deficits in morphine-withdrawn male rats

Abstract

Abstinence from morphine in patients with opioid use disorder leads to both physical and emotional withdrawal symptoms. A common treatment strategy involves administering long-acting opioids to alleviate these symptoms while gradually reducing the dose, helping patients adapt to morphine-free conditions. This study examined how tapering regimens of methadone, buprenorphine, or morphine affect anxiety-like behaviors and social functioning in morphine-dependent rats. Male Wistar rats were rendered morphine-dependent over a 10-day period and subsequently treated for 30 days with gradually decreasing doses of methadone, buprenorphine, or morphine. Anxiety-like behavior was assessed using the elevated plus maze (EPM), while social behaviors were evaluated through a three-chamber test. The results showed that morphine-abstinent rats exhibited increased anxiety-like behavior in the EPM. Chronic treatment with methadone or morphine tapering reversed this anxiogenic effect, whereas buprenorphine reduced locomotor activity without mitigating anxiety. Although all groups, including morphine-abstinent rats, displayed normal sociability, the abstinent rats lacked a preference for social novelty. Only methadone tapering restored this deficit in social novelty preference. The present results suggest that gradual methadone reduction may be the best treatment for anxiety and social deficits caused by morphine withdrawal. Further research is needed to confirm these effects and their clinical relevance for opioid addiction treatment.

Keywords: Anxiety; Buprenorphine; Methadone; Morphine abstinence; Sociability; Social novelty preference.