TY - JOUR
T1 - Analgesic potency of TRIMU-5
T2 - A mixed μ2 opioid receptor agonists/μ1 opioid receptor antagonist
AU - Tive, Leslie A.
AU - Pick, Chaim G.
AU - Paul, Dennis
AU - Roques, Bernard P.
AU - Gacel, Gilles A.
AU - Pasternak, Gayril W.
N1 - Funding Information:
This work was supported, in part, by grants from the National Intitute on Drug Abuse to GWP (DA02615 and DA07242). G.W.P. is a recipient of a Research Career Development Award from NIDA (DA00138). D.P. was supported by a Fellowship from the Pharmaceutical Manufacturers Association Foundation.
PY - 1992/6/5
Y1 - 1992/6/5
N2 - 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.
AB - 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.
KW - Opiate analgesia
KW - Opioid receptors (mixed agonist/antagonist)
KW - μ-Opioid receptors
UR - http://www.scopus.com/inward/record.url?scp=0026748921&partnerID=8YFLogxK
U2 - 10.1016/0014-2999(92)90367-D
DO - 10.1016/0014-2999(92)90367-D
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AN - SCOPUS:0026748921
SN - 0014-2999
VL - 216
SP - 249
EP - 255
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2
ER -