Psychopharmacology (1999) 144 : 239–247 © Springer-Verlag 1999 ORIGINAL INVESTIGATION Charles D. Cook · Joshua S. Rodefer Mitchell J. Picker Selective attenuation of the antinociceptive effects of μ opioids by the putative dopamine D 3 agonist 7-OH-DPAT Received : 30 June 1998 / Final version : 12 January 1999 Abstract Rationale : The purpose of the present investigation was to evaluate the effects of the D 3 agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH- DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of  opioids. Methods : Antinociception was assessed using a warm- water tail-withdrawal procedure in rats. Results : The  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 D 3 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 D 3 /D 2 agonist ()- quinpirole (0.1–10 mg/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 D 2 /D 3 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 D 1 agonist (±)-SKF38393 (1.0 and 10 mg / kg) and the D 1 antag- onist (+)-SCH23390 (0.1 and 1.0 mg / kg) failed to alter the morphine dose-effect curve. Conclusion : 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 D 3 , and pos- sibly the D 2 , receptor can modulate  agonist-induced antinociception. Key words Dezocine · Morphine · 7-OH-DPAT · Quinpirole · SKF38393 · SCH23390 · Rat · Warm-water tail-withdrawal · Antinociception Introduction The DA D 3 receptor is considered part of the D 2 -like family of receptors (Sokoloff et al. 1990) and is located both presynaptically as an autoreceptor and postsy- naptically (Bouthenet et al. 1991). Although the behav- ioral and physiological consequences of activating the postsynaptic D 3 receptor are not clear, activity at the D 3 presynaptic autoreceptor is believed to inhibit the release of DA. Indeed, systemic administration of the putative D 3 agonist 7-OH-DPAT produces a dose- and time-dependent decrease in electrically stimulated DA release (Gilbert et al. 1995) and can block increased levels of DA produced by the administration of cocaine (Parsons et al. 1996) and DA antagonists (Gainetdinov et al. 1996). Recently, 7-OH-DPAT has been reported to prevent the acquisition of a morphine conditioned place pref- erence (De Fonseca et al. 1995), attenuate morphine- induced locomotion (Suzuki et al. 1995), and attenuate the discriminative stimulus effects produced by  opi- oids (Cook and Picker 1998). Because  opioids are known to stimulate the release of DA (Iyengar et al. 1987; Di Chiara and Imperato 1988), it has been pos- tulated that presynaptic activity at the D 3 autoreceptor by 7-OH-DPAT may be responsible for the attenuation of the effects of morphine. That 7-OH-DPAT attenu- ates a diverse set of  opioid-induced behaviors that have distinct anatomical loci of actions suggests that C.D. Cook (*) · J.S. Rodefer 1 · M.J. Picker Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3270, USA e-mail : ccook@email.unc.edu Fax : +1-919-962-2537 Present address : 1 Harvard Medical School, New England Regional Primate Research Center, Division of Behavioral Biology, Box 9102, One Pine Hill Drive, Southborough, MA 01772-9102, USA