Novel Endomorphin Analogs are More Potent and Longer Lasting Analgesics in Neuropathic, Postoperative, Inflammatory, and Visceral Pain Relative to Morphine.

Amy K Feehan
Jenny Morgenweck, The Jackson Laboratory
Xing Zhang
Ariel Amgott-Kwan
James E Zadina


Activation of the mu-opioid receptor provides the gold standard for pain relief, but a majority of opioids used clinically have adverse effects that have contributed to an epidemic of overdose deaths. We recently characterized mu-opioid receptor selective endomorphin (EM) analogs that provide potent antinociception with reduction or absence of a number of side effects of traditionally prescribed opioids including abuse liability, respiratory depression, motor impairment, tolerance, and inflammation [91]. The current study explores the effectiveness of these EM analogs relative to morphine in four major pain models by both intrathecal and intravenous administration in male, Sprague-Dawley rats and male CD-1 mice. In the spared nerve injury (SNI) model of neuropathic pain, mechanical allodynia and mechanical hyperalgesia were assessed with von Frey and Randall-Selitto tests, respectively. In the paw incision model of postoperative pain, von Frey testing was used to assess mechanical allodynia and thermal hyperalgesia was evaluated with Hargreaves testing. In the Complete Freund's Adjuvant (CFA) model of inflammatory pain, thermal hyperalgesia was assessed by Hargreaves testing. In CD-1 mice, visceral pain was assessed with the acetic acid writhing test. In all cases, EM analogs had equal or greater potency and longer duration of action relative to morphine. The data suggest that EM analogs, particularly analog 4 (ZH853), could provide effective therapy for a diverse spectrum of pain conditions with low risk of the adverse side effects compared to currently used opioids such as morphine. J Pain 2017 Sep 19 [Epub ahead of print]