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Abstract
Modulation of the glutamatergic system has been shown to alter development of opioid tolerance and the subsequent tolerant state generated by chronic treatment. It is not known, however, whether glutamate receptors are involved in immune tolerance, specifically, tolerance to T lymphocyte suppression by morphine. The studies described in this dissertation examine the role of NMDA receptors on the immunomodulatory effect of chronic or sub-chronic morphine treatment as determined by proliferative response of peripheral blood lymphocytes to a T-cell mitogen following morphine challenge (10mg/kg, s.c.). The results demonstrate that antagonism of NMDA receptors, with the non-competitive NMDA receptor antagonist, MK-801 (0.1mg/kg, s.c.), during chronic morphine delays, but does not fully attenuate, the rate of development of immunologic tolerance to morphine challenge. Additionally, activation of central NMDA receptors with microinjections of NMDA (1nmol; i.c.v.) into the lateral ventricle accelerated the rate of tolerance development to the suppressive effect of morphine challenge on mitogen-induced lymphocyte proliferation. Subsequently, when the protein kinase inhibitor, H7 (25nmol; i.c.v.), was centrally administered concurrent to central NMDA, animals once again showed suppression of T lymphocytes from morphine challenge, suggesting protein kinases may be involved in the acceleration of immunologic tolerance by central NMDA receptor activation.
In determining a possible peripheral mechanism mediating glutamatergic influence on lymphocyte proliferation, in vitro glutamate (ED50 ≈ 10−6M) and NMDA (ED50 ≈ 10−3M) were found to dose-dependently suppress proliferation of peripheral blood lymphocytes. This suppression was dose-dependently antagonized by in vitro MK-801. However, RT-PCR and Western Blot analysis failed to detect evidence of mRNA or protein expression of NMDA receptors on isolated lymphocytes. Furthermore, acute or chronic MK-801 was unable to alter T lymphocyte suppression by acute morphine, suggesting that it was the chronic presence of MK-801, combined with morphine, which mediated the altered kinetics of immunomodulatory tolerance.
It was then determined whether presence of MK-801 altered the morphine-tolerant state as tolerance to T lymphocyte suppression subsequent to 10 days of treatment revealed no apparent alteration by the antagonist. (Abstract shortened by UMI.)
