Abstract
δ-Opioid receptor-selective agonists produce antinociception and convulsions in several species, including mice. This article examines two hypotheses in mice: 1) that antinociception and convulsive activity are mediated through the same type of δ-receptor and 2) that greater δ-agonist efficacy is required for antinociception than for convulsive activity. δ-Mediated antinociception was evaluated in the acetic acid-induced abdominal constriction assay, which involves a low-intensity noxious stimulus; convulsive activity was indicated as a mild tonic-clonic convulsive episode followed by a period of catalepsy. In δ-opioid receptor knockout mice [DOR-1(−/−)], the nonpeptidic δ-agonists (±)-4-[(R*)-[(2S*,5R*)-2,5-dimethyl-4-(2-propenyl)-1- piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride (BW373U86) and (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N, N-diethylbenzamide (SNC80) failed to produce convulsive behavior demonstrating the absolute involvement of DOR-1 in this effect. In NIH Swiss mice expressing δ-opioid receptors, BW373U86 produced both antinociception and convulsive activity. These effects were antagonized by the putative δ1-receptor-selective antagonist 7-benzylidenenaltrexone and the putative δ2-receptor-selective antagonist naltriben. Tolerance developed to both the convulsive and antinociceptive effects of BW373U86. Tolerance to the convulsive, but not the antinociceptive, effects of BW373U86 was largely prevented when the antagonist naltrindole was given 20 min after each dose of the agonist in a 3-day treatment paradigm. The convulsive action of BW373U86 was also less sensitive than the antinociceptive action to treatment with the irreversible δ-antagonist naltrindole isothiocyanate. Collectively, these data suggest that the convulsive and antinociceptive activities of δ-agonists are mediated through the same receptor but that the receptor reserve for δ-mediated convulsive activity is greater than for δ-mediated antinociceptive activity.
Footnotes
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United States Public Health Service grants supported this work as follows: GM-07767 and T32-DA07267 (D.C.B.), F32-DA-05964 and T32-MH/AG-19957 (J.F.N.), DA-09040 (J.E.P.), DK-059501 (K.C.R.), and DA-00254 (J.H.W. and J.R.T.).
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DOI: 10.1124/jpet.102.036525
- Abbreviations:
- BW373U86
- (±)-4-[(R*)-[(2S*,5R*)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride
- SNC80
- (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide
- BU48
- N-cyclopropylmethyl-[7α,8α,2′,3′]-cyclohexano-1′[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine
- BNTX
- 7-benzylidenenaltrexone
- NTB
- naltriben
- 5′-NTII
- 5′-naltrindole isothiocyanate
- DPDPE
- [d-Pen2,d-Pen5]enkephalin
- CI
- confidence interval
- Received February 20, 2002.
- Accepted August 7, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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