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Agents that enhance gamma-aminobutyric acid (GABA) neurotransmission can modulate certain effects of opioids, such as analgesia. In this study, the interaction between morphine and GABAergic agents on the release of [3H]norepinephrine ([3H]NE) from rat frontal cortical slices was examined. GABA (10(-4) M), enhanced potassium-stimulated [3H]NE release and reversed the inhibitory effect of 10(-6) M morphine. GABA and muscimol modulated the inhibitory effect of morphine in a noncompetitive manner. Bicuculline methiodide (10(-4) M) reduced the effect of GABA in the absence of morphine, and appeared to reduce the effect of GABA in the presence of morphine, although the latter effect was not statistically significant from the controls. While the GABAA agonist muscimol mimicked the effect of GABA, the GABAB agonist baclofen did not affect the release of [3H]NE in the absence or the presence of 10(-6) M morphine. These results support the involvement of GABAA receptors in modulating the action of opioids on the noradrenergic system in the cerebral cortex of the rat.

Antibodies that specifically recognize and bind opiate receptors were developed by the anti-idiotypic method. Antimorphine antibodies were generated in rabbits and showed selective binding to various opiate ligands. Guinea pigs were immunized with antimorphine antibodies to produce anti-idiotypic antibodies that cross-reacted with opiate receptors. Guinea pig antiserum inhibited binding of naloxone (0.6 nmol) to mouse brain homogenate. In isolated mouse vas deferens, contraction of electrically stimulated tissue was inhibited by the antiserum. The results indicate that anti-idiotypic antibodies which interact with opiate receptors were developed without isolating receptors.

The role of the immune system in the development of physical dependence and tolerance to morphine was studied in mice in which the immune response was either stimulated or suppressed. Immunization of mice against morphine increased the blood and brain levels of morphine as compared to controls. However, the development of physical dependence and tolerance was decreased. The chronic responses to morphine were also decreased by nonspecific immunosuppression (vincristine-cyclophosphamide treatment and gamma-irradiation exposure) and specific immunosuppression (antithymocyte and antilymphocyte sera treatment). Immunosuppressive treatments did not alter the rate of morphine absorption from the subcutaneous depot used to induce chronic exposure to the drug. However, the blood and brain levels of morphine were higher than control after 72 hours of morphine pellet implantation. It is apparent that manipulation of the immune system can alter the physical dependence and tolerance development to morphine.

Anti-idiotypic antibodies which recognize the opiate receptor were generated in guinea pigs following immunization against purified rabbit anti-morphine antibodies. The anti-idiotypic antibodies produced a concentration-dependent inhibition of [3H]naloxone binding to opiate receptors in a membranous mouse brain preparation. Saturation analysis indicated that the antibodies produced a non-competitive inhibition of naloxone binding. The ability of the antibodies to interact with biological systems was investigated in in vitro systems. In both the isolated guinea pig ileal longitudinal muscle and mouse vas deferens, the antibodies produced a concentration-dependent, opiate agonist-like action. The anti-morphine anti-idiotypic antibodies appear to interact specifically with the opiate receptor and may serve as useful tools in characterization of this receptor system.