Analgesic potency of TRIMU-5: A mixed μ(2) opioid receptor agonists/μ(1) opioid receptor antagonist Journal Article
| Authors: | Tive, L. A.; Pick, C. G.; Paul, D.; Roques, B. P.; Gacel, G. A.; Pasternak, G. W. |
| Article Title: | Analgesic potency of TRIMU-5: A mixed μ(2) opioid receptor agonists/μ(1) opioid receptor antagonist |
| 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. © 1992. |
| Keywords: | unclassified drug; drug activity; nonhuman; mouse; animal; mice; animal tissue; animal experiment; dose-response relationship, drug; drug receptor binding; rat; binding sites; rats; receptor affinity; rats, sprague-dawley; morphine; analgesics; oligopeptides; analgesia; receptors, opioid, mu; opiate receptor; beta funaltrexamine; gastrointestinal transit; opiate antagonist; naloxonazine; opiate agonist; intracerebroventricular drug administration; male; priority journal; article; enkephalin derivative; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; intrathecal drug administration; opiate analgesia; μ-opioid receptors; opioid receptors (mixed agonist/antagonist); trimu 5 |
| Journal Title: | European Journal of Pharmacology |
| Volume: | 216 |
| Issue: | 2 |
| ISSN: | 0014-2999 |
| Publisher: | Elsevier B.V. |
| Date Published: | 1992-06-05 |
| Start Page: | 249 |
| End Page: | 255 |
| Language: | English |
| DOI: | 10.1016/0014-2999(92)90367-d |
| PUBMED: | 1327812 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 30 July 2019 -- Source: Scopus |
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