Abstract Electrical stimulation of the ventral midbrain in freely moving rats led to an antinociception against both noxious heat and noxious pressure. Recurrent stimulation was associated with a progressive loss of the antinociceptive efficacy of stimulation. Rats adapted (“tolerant”) to stimulation revealed a significant reduction in the antinociceptive potency of a low dose of the systemically applied selective μ-opioid agonist, morphine. In distinction, the antinociceptive effect of the selective κ-agonist, trans- 3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488H) was not modified. In the presence of naloxone, delivered subcutaneously via minipumps at a low dose for 7 days, the antinociceptive action of morphine was abolished, whereas that of U50488H was not attenuated: this reflects the selective blockade of μ-receptors. Rats receiving naloxone failed to develop an antinociception upon midbrain electrical stimulation. Removal of the pumps led to a supersensitivity to the antinociceptive effects of morphine but not U50488H. Similarly, midbrain stimulation-produced antinociception was enhanced. These data demonstrate that (1) midbrain stimulation-produced analgesia is selectively cross-tolerant to a μ- as compared to a κ-agonist (2) a very low dose of naloxone selective for the μ-receptor blocks midbrain stimulation-produced analgesia, and (3) chronic naloxone treatment leads to a selective supersensitivity to a μ-agonist as compared to a κ-agonist and an enhancement of midbrain stimulationproduced analgesia. Collectively, the data indicate that a μ-opioid receptor mediates midbrain stimulation-produced analgesia in the rat against both noxious heat and noxious pressure.