Analgesic potency of TRIMU-5: A mixed μ2 opioid receptor agonists/μ1 opioid receptor antagonist

Leslie A. Tive, Chaim G. Pick, Dennis Paul, Bernard P. Roques, Gilles A. Gacel, Gayril W. Pasternak

Research output: Contribution to journalArticlepeer-review

Abstract

TRIMU-5 (Try-D-Ala-Gly-NH-(CH2)2CH(CH3)2) is a potent enkephalin analog with analgesic actions. Detailed studies show high affinity for both μ1 and μ2 sites, with poor affinity for σ, ν1 and ν3 receptors. Of all the μ ligands examined in binding assays, TRIMU-5 was the most μ-selective. In mice, TRIMU-5 administered either intracerebroventricularly (i.c.v.) or intrathecally elicited analgesia which was readily reversed by the μ-selective antagonist β-funaltrexamine (β-FNA). However, the analgesia observed following i.c.v. injections differed from traditional μ 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 β-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 μ2 receptors. TRIMU-5 did have supraspinal actions, inhibiting gastrointestinal transit, another μ2 action. In binding studies TRIMU-5 had high affinity for μ1 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 μ2 opioid receptor agonist/μ1 opioid receptor antagonist.

Original languageEnglish
Pages (from-to)249-255
Number of pages7
JournalEuropean Journal of Pharmacology
Volume216
Issue number2
DOIs
StatePublished - 5 Jun 1992
Externally publishedYes

Keywords

  • Opiate analgesia
  • Opioid receptors (mixed agonist/antagonist)
  • μ-Opioid receptors

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