Endomorphin analogs CEMR-1 and CEMR-2 administered intravenously display potent antinociception with limited tolerance in acute, neuropathic and inflammatory pain.

Endomorphins (EMs) hold substantial promise as therapeutic agents for pain management. Our earlier investigations established that the novel EMs analogs CEMR-1 and CEMR-2 acted as potent and selective μ-opioid receptor agonists, displaying marked analgesic properties at the central level. This study aimed to evaluate the analgesic effects and tolerance profiles of CEMR-1 and CEMR-2 following intravenous (i.v.) administration across a range of preclinical pain models. Following tail vein injection, CEMR-1 and CEMR-2 produced potent and prolonged analgesia in acute pain, with minimal acute or chronic tolerance and no cross-tolerance to morphine. Among them, CEMR-1 particularly demonstrated potential as a non-tolerance-forming analgesic. Antagonist experiments further confirmed that the analgesic effects of these two analogs were primarily mediated by central opioid receptors. Furthermore, in neuropathic and inflammatory pain models, both analogs also exhibited notable analgesic efficacy after i.v. administration along with reduced tolerance-related side effects. Importantly, under neuropathic pain conditions, CEMR-1 and CEMR-2 almost did not induce chronic tolerance to their analgesic effects. The findings of this study demonstrated that the novel EMs analogs CEMR-1 and CEMR-2 exerted strong and sustained analgesic effects administered systemically and reduced tolerance. Therefore, CEMR-1 and CEMR-2 were promising candidate analgesics with minimal adverse effect of tolerance.