Quaternary naltrexone: its immunomodulatory activity and interaction with brain delta and kappa opioid receptors

To investigate the role of brain opioid receptors in immune reactions, quaternary naltrexone (QNtx), a nonselective opioid antagonist which does not cross the brain-blood barrier, was tested for its immunomodulatory activity and ability to antagonize immunological changes produced by centrally applied delta-receptor agonist methionine-enkephalin (Met-Enk) and kappa-opioid receptor agonist MR 2034. Plaque-forming cell (PFC) response served as an immunological model. For this purpose, different groups of Wistar rats were centrally (intracerebroventricularly, i.c.v.) and peripherally (intraperitoneally, i.p., or subcutaneously, s.c.) treated with different doses of Met-Enk, MR 2034 and QNtx. Centrally injected Met-Enk and MR 2034 induced a dose-dependent potentiation and suppression of PFC response, respectively. Small amounts of i.c.v. given QNtx produced a dose-dependent increase in the number of PFC, whereas peripherally administered antagonist potentiated immune response in a dose-independent manner. A dose of 10 μg/kg of QNtx given i.c.v. completely abolished the immunopotentiation by Met-Enk. However, a large dose of 5 mg/kg of QNtx given s.c., did not affect the Met-Enk-induced immunoenhancement. Immunosuppression produced by i.c.v. injected MR 2034 was totally abrogated by prior i.c.v. application of QNtx, but partially blocked by s.c. administration of the antagonist. These results suggest that: (a) QNtx itself potentiates the humoral immune response when applied centrally in small doses (1 to 10 μg/kg) or peripherally in relativelly large doses (0.2 to 5 mg/kg), (b) immunopotentiation and immunosuppression induced by i.c.v. given Met-Enk and MR 2034, respectively, appears to be preferentially mediated through brain opioid receptors, (c) QNtx antagonizes the immunomodulating activities of Met-Enk and MR 2034, and (d) peripheral opioid systems may also contribute to the immunomodulation evoked by centrally administered kappa-receptor agonist MR 2034. As a whole, this study provides evidence for the involvement of the central opioid system in mechanisms underlying the immune responsiveness.