The dopamine D3/2 agonist 7-OH-DPAT attenuates the development of morphinetolerance but not physical dependence in rats

Rationale: The dopamine (DA) D3/2 agonist 7-OH-DPAT attenuates the acute an tinociceptive, discriminative stimulus, locomotor activating, and reinforci ng effects of mu agonists (for example, morphine). Objectives. To examine t he ability of 7-OH-DPAT to modulate the development of morphine tolerance a nd physical dependence in the rat. Methods: Morphine antinociception was as sessed using a warm water tail-withdrawal procedure before and following ch ronic treatment with morphine (15 mg/kg)/7-OH-DPAT (0.3-3.0 mg/kg). Physica l dependence was assessed following naloxone-precipitated (1.0 mg/kg) withd rawal in rats treated chronically with morphine (15 and 7.5 mg/kg)/7-OH-DPA T (1.0-10 mg/kg). Results: 7-OH-DPAT attenuated the antinociceptive effects of morphine in both morphine naive and tolerant rats. Additionally, morphi ne tolerance was attenuated by the coadministration of 7-OH-DPAT in a dose- and time-dependent manner. The magnitude of the attenuation obtained when morphine and 7-OH-DPAT were administered at the same time was similar to th at obtained when administration of these drugs was separated by 6 h, indica ting that 7-OH-DPAT did not alter morphine pharmacokinetics. In rats render ed tolerant to morphine, the subsequent coadministration of morphine/7-OH-D PAT failed to reverse morphine tolerance, but did attenuate its further dev elopment. The level of physical dependence (number and frequency of withdra wal signs) was greater in rats treated with 15 than 7.5 mg/kg morphine. Und er both treatment conditions, physical dependence was not altered by 7-OH-D PAT. In morphine-dependent (15 mg/kg) rats, 7-OH-DPAT (3.0 and 10 mg/kg) fa iled to precipitate withdrawal. Conclusion: The D3/2 agonist 7-OH-DPAT can attenuate the antinociceptive effects of morphine in both acute and chronic preparations as well as the development of morphine tolerance. 7-OH-DPAT d oes not, however, alter morphine physical dependence.