Selective attenuation of the antinociceptive effects of mu opioids by the putative dopamine D3 agonist 7-OH-DPAT.
BACKGROUND
The purpose of the present investigation was to evaluate the effects of the D3 agonist (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of mu opioids.


METHODS
Antinociception was assessed using a warm-water tail-withdrawal procedure in rats.


RESULTS
The mu opioids morphine (0.3-10 mg/kg) and dezocine (0.03-3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D3 agonist 7-OH-DPAT (1.0-10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D3/D2 agonist (-)-quinpirole (0.1-10mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D2/D3 antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D1 agonist (+/-)-SKF38393 (1.0 and 10 mg/kg) and the D1 antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve.


CONCLUSIONS
The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D3, and possibly the D2, receptor can modulate mu agonist-induced antinociception.
Cook
C D
CD
Department of Psychology, University of North Carolina at Chapel Hill, 27599-3270, USA. ccook@email.unc.edu
Rodefer
J S
JS
Picker
M J
MJ
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003516:Cycloparaffins / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004336:Drug Antagonism; D008297:Male; D009020:Morphine / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013134:Spiperone / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000701:Analgesics, Opioid; D001552:Benzazepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003516:Cycloparaffins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017450:Receptors, Opioid, mu; D013764:Tetrahydronaphthalenes; D019257:Quinpirole; D013134:Spiperone; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D009020:Morphine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; C010827:dezocine