Endomorphin analog ZH853
Experience the future of the Tulane University Digital Library.
We invite you to visit the new Digital Collections website.
Description
Opioids are crucial for treating moderate to severe pain, but their addictive properties have contributed to dramatic increases in misuse, abuse, and overdose deaths. Opioid agonist medications for opioid use disorder also possess adverse effects and, despite treatment, rates of relapse remain high. We previously showed the analgesic potential and low abuse liability of endomorphin analog ZH853 in male rodents. The studies presented here further examine the analgesic-like effects of ZH853 while examining side-effects contributing to addiction potential. We investigated antinociceptive, antihyperalgesic, and antiallodynic effects in female and male rodents using validated models of postoperative, inflammatory, and visceral pain. We extended previous findings on the low abuse potential of ZH853 by examining dependence liability, rewarding properties in females, and reinforcing effects in male rats with previous opioid exposure. Lastly, we evaluated the potential use of ZH853 as a treatment for opioid use disorder by examining its effect on opioid-seeking behavior and its ability to mitigate somatic signs of opioid withdrawal. We found that intravenous ZH853 provided antinociception, reversed inflammatory hyperalgesia, inhibited postoperative allodynia, and was not self-administered by female rats. Relative to morphine, ZH853 also led to comparable somatic signs of withdrawal, but with low withdrawal anhedonia, and absent associated changes in ventral tegmental area KCC2 expression. The low abuse liability of ZH853 was further supported in oxycodone self-administering male rats, where ZH853 substitution did not maintain opioid-seeking behavior. Finally, ZH853 inhibited opioid relapse responding following forced abstinence, and blunted the expression of morphine withdrawal. Collectively, the outcomes of these studies support the development of ZH853 as a safer opioid medication for acute and long-term treatment of pain and opioid use disorder.