Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine

Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions. Separation of analgesia from unwanted effects has long been an unmet goal of opioid research. Novel MOR agonist structures may prove critical for greater success. Here we tested metabolically stable analogs of the endomorphins, endogenous opioids highly selective for the MOR. Compared to morphine, the analogs showed dramatically improved analgesia-to-side-effect ratios. At doses providing equal or greater antinociception than morphine in the rat, the analogs showed reduced a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in both conditioned place preference and self-administration tests. Differential effects on glial activation indicate a mechanism for the relative lack of side effects by the analogs compared to morphine. The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine.