Endomorphin analog ZH853 shows low reward, tolerance, and affective-motivational signs of withdrawal, while inhibiting opioid withdrawal and seeking.

Currently available μ-opioid receptor agonist pharmacotherapies for opioid use disorder possess adverse effects limiting their use and, despite treatment, rates of relapse remain high. We previously showed that endomorphin analog ZH853 had no effect in rodent models that predict abuse liability in humans. Here we extended these findings by examining dependence liability and reinforcing properties in female rats and male rats with previous opioid exposure. The potential use of ZH853 in managing opioid use disorder was evaluated by examining its effect on opioid-seeking behavior and withdrawal. We found that ZH853 did not induce locomotor activation in male and female mice and was not self-administered by female rats. Relative to morphine, ZH853 led to similar somatic signs of withdrawal, but low affective-motivational signs of withdrawal, and absent changes in ventral tegmental area K(+)-Cl(-) co-transporter expression associated with reward dysregulation. The low abuse liability of ZH853 was further supported in oxycodone self-administering male rats, where ZH853 substitution extinguished opioid-seeking behavior. ZH853 priming also did not reinstate morphine conditioned place preference. Lastly, ZH853 inhibited oxycodone-seeking behavior during relapse after forced abstinence and decreased the expression of morphine withdrawal. These findings suggest the potential use of ZH853 as a safer opioid medication for long-term treatment of pain and opioid use disorder.