ROLE OF CENTRAL OPIOID RECEPTOR SUBTYPES IN MORPHINE-INDUCED ALTERATIONS IN PERIPHERAL LYMPHOCYTE ACTIVITY

Morphine has been shown to decrease proliferative responses of rat T-l ymphocytes via central opioid receptors, however, the specific recepto r subtype(s) mediating this effect have not been established. To deter mine the potential role of central mu opioid receptors in morphine-med iated suppression of T-lymphocyte proliferation, 20 nmol/2 mu l of eit her morphine sulfate or DAMGO (mu-selective agonist) were administered into the lateral ventricle of freely moving Sprague-Dawley rats. Lymp hocyte proliferative response to the polyclonal T cell mitogen concana valin A (ConA), changes in splenic natural killer cell (NK) cytolytic activity, activation of the hypothalamic-pituitary-adrenal (HPA) axis and antinociception (tail-flick latency) were examined. Results indica ted that like morphine, DAMGO decreased blood lymphocyte proliferative responses by 80% and elevated both tail-flick latency and plasma cort icosterone when compared to saline-treated animals. The proliferation response of lymphocytes from the spleen or thymus and splenic NK cell activity were not significantly altered by either morphine or DAMGO tr eatment. The effects of DAMGO were determined to be dose-dependent and completely antagonized by naltrexone pretreatment. Central administra tion of DPDPE (delta-selective agonist) and U-50488 (kappa-selective a gonist) produced between 40-50% suppression of blood lymphocyte prolif eration responses only at a dose five times greater (100 nmol) than DA MGO treatment, without altering antinociception or activation of the H PA axis. To determine the central opioid receptor subtype(s) involved in the effects of morphine, selective opioid antagonists were microinj ected into the lateral ventricle prior to morphine treatment (6 mg/kg, s.c.). CTOP (mu-selective antagonist, 5 mu g/2 mu l) completely block ed the effects of morphine on all parameters measured, however, naltri ndole (delta-selective antagonist, 2 mu g/2 mu l) or nor-binaltorphimi ne (kappa-selective antagonist, 73.5 mu g/2 mu l) failed to block the effects of morphine. Collectively, these results provide evidence that morphine acts primarily through central mu receptors to modulate peri pheral blood lymphocyte proliferation responses. Further, the antinoci ception and blood lymphocyte effects show greater sensitivity to opioi ds than either natural killer cell cytolytic activity or activation of the HPA axis. (C) 1998 Elsevier Science B.V.