Analgesic potency of TRIMU-5: a mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist

Eur J Pharmacol. 1992 Jun 5;216(2):249-55. doi: 10.1016/0014-2999(92)90367-d.


TRIMU-5 (Tyr-D-Ala-Gly-NH-(CH2)2CH(CH3)2) is a potent enkephalin analog with analgesic actions. Detailed studies show high affinity for both mu 1 and mu 2 sites, with poor affinity for delta, kappa 1 and kappa 3 receptors. Of all the mu ligands examined in binding assays, TRIMU-5 was the most mu-selective. In mice, TRIMU-5 administered either intracerebroventricularly (i.c.v.) or intrathecally elicited analgesia which was readily reversed by the mu-selective antagonist beta-funaltrexamine (beta-FNA). However, the analgesia observed following i.c.v. injections differed from traditional mu ligands: (1) the dose of drug required for analgesic activity i.c.v. was 100-fold greater than those following intrathecal administration; (2) although sensitive to beta-FNA, the analgesia was not antagonized by naloxonazine; and (3) the analgesia was reversed by an opioid antagonist given intrathecally (i.t.) but not i.c.v. Thus, TRIMU-5 analgesia appeared to be mediated spinally through mu 2 receptors. TRIMU-5 did have supraspinal actions, inhibiting gastrointestinal transit, another mu 2 action. In binding studies TRIMU-5 had high affinity for mu 1 sites, but pharmacological studies revealed antagonist actions at this receptor. In mice, the analgesia produced by morphine given i.c.v. was antagonized by coinjection of a low TRIMU-5 dose which was inactive alone. Similarly, TRIMU-5 coadministered with morphine into the periaqueductal gray of rats reversed the analgesia seen with morphine alone. Thus, TRIMU-5 is a highly selective mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Gastrointestinal Transit / drug effects
  • Male
  • Mice
  • Morphine / pharmacology*
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / classification
  • Receptors, Opioid, mu / drug effects*


  • Analgesics
  • Oligopeptides
  • Receptors, Opioid, mu
  • Morphine
  • TRIMU 5