Antagonist-induced opioid receptor up-regulation. II. Regionally specific modulation of mu, delta and kappa binding sites in rat brain revealed by quantitative autoradiography.

The neurochemical basis for the supersensitivity to mu or kappa opiate agonists observed after chronic naloxone infusion (reported in the preceding paper) has been investigated using the technique of quantitative in vitro autoradiography. The binding of [3H]-D-Ala2MePhe4Glyol enkephalin (3H-DAGO) to mu opioid sites was increased in many brain regions after chronic administration (7 days) of a low dose of naloxone (0.5 mg/kg/hr). The greatest increases were seen in the hippocampal strata moleculare and lucidum. The binding of [3H]-D-Ala2-D-Leu5 enkephalin (3H-DADL) to delta sites and of [3H]-bremazocine to kappa sites were not significantly affected in any region. In contrast, after administration of a higher dose of naloxone (3.0 mg/kg/hr), the binding to mu, delta and kappa sites was increased in many brain areas, suggesting that up-regulation is observed only when a sufficient proportion of the receptors in vivo are occupied by the antagonist. However, a different regional pattern of up-regulation was seen for each class of opiate binding site. The greatest increases in kappa binding in the brain were seen in the periaqueductal gray and the hippocampal molecular and pyramidal cell layers. The substantia nigra showed up-regulation of kappa but not of mu sites. Differences in the pattern of mu and kappa binding site up-regulation were also noted in the spinal cord. This regionally specific modulation of opiate binding sites suggests that, for each receptor type, the level of tonic activation varies between individual brain areas. In addition, the data demonstrate that all three types of opiate receptor can undergo up-regulation "in vivo."