Abstract
3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-β-D-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of μ-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [D-Ala2,N-Me-Phe 4,Gly5-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at μ-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.
| Original language | English |
|---|---|
| Pages (from-to) | 1030-1039 |
| Number of pages | 10 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 308 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2004 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys. / Platt, Donna M.; Rowlett, James K.; Izenwasser, Sari E; Spealman, Roger D.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 308, No. 3, 01.03.2004, p. 1030-1039.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys
AU - Platt, Donna M.
AU - Rowlett, James K.
AU - Izenwasser, Sari E
AU - Spealman, Roger D.
PY - 2004/3/1
Y1 - 2004/3/1
N2 - 3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-β-D-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of μ-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [D-Ala2,N-Me-Phe 4,Gly5-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at μ-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.
AB - 3-O-Methylnaltrexone (3-MNTX), a putative antagonist of morphine-6-β-D-glucuronide (M6G) receptors, has been reported to block the behavioral effects of heroin at doses that do not block those of morphine, suggesting that M6G receptors may play a unique role in the addictive properties of heroin. This study investigated the effects of 3-MNTX in monkeys trained to discriminate i.v. heroin from vehicle or to self-administer i.v. heroin under a progressive-ratio schedule. Additional in vitro studies determined the effects of 3-MNTX and reference drugs on adenylyl cyclase activity in caudate-putamen membranes of monkeys and rats. In drug discrimination experiments, heroin, morphine, and M6G substituted for heroin in all subjects, whereas 3-MNTX substituted for heroin in one-half the monkeys tested. In these latter monkeys, the effects of 3-MNTX were antagonized by naltrexone, and pretreatment with 3-MNTX enhanced the effects of heroin, M6G, and morphine, indicative of μ-agonist activity. In monkeys showing no substitution of 3-MNTX for heroin, 3-MNTX antagonized the effects of heroin, M6G, and morphine. In self-administration experiments, heroin and 3-MNTX maintained injections per session significantly above those maintained by vehicle when the initial response requirement (IRR) was low; only heroin maintained significant self-administration when the IRR was high. In vitro, 3-MNTX inhibited adenylyl cyclase activity in both monkey and rat brain membranes. The degree of inhibition produced by 3-MNTX was less than that produced by the full agonist [D-Ala2,N-Me-Phe 4,Gly5-ol]-enkephalin (DAMGO). The results suggest that 3-MNTX functions primarily as a partial agonist at μ-receptors in monkeys and do not support a singular role for M6G receptors in the abuse-related effects of heroin.
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UR - http://www.scopus.com/inward/citedby.url?scp=1342344543&partnerID=8YFLogxK
U2 - 10.1124/jpet.103.060962
DO - 10.1124/jpet.103.060962
M3 - Article
C2 - 14634035
AN - SCOPUS:1342344543
VL - 308
SP - 1030
EP - 1039
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -