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-lymphocytes via central opioid receptors, however, the specific receptor subtype(s) mediating this effect have not been established. To determine the potential role of central mu opioid receptors in morphine-mediated suppression of T-lymphocyte proliferation, 20 nmol/2 microliters of either morphine sulfate or DAMGO (mu-selective agonist) were administered into the lateral ventricle of freely moving Sprague-Dawley rats. Lymphocyte proliferative response to the polyclonal T cell mitogen concanavalin 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 indicated that like morphine, DAMGO decreased blood lymphocyte proliferative responses by 80% and elevated both tail-flick latency and plasma corticosterone 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 treatment. The effects of DAMGO were determined to be dose-dependent and completely antagonized by naltrexone pretreatment. Central administration of DPDPE (delta-selective agonist) and U-50488 (kappa-selective agonist) produced between 40-50% suppression of blood lymphocyte proliferation responses only at a dose five times greater (100 nmol) than DAMGO treatment, without altering antinociception or activation of the HPA axis. To determine the central opioid receptor subtype(s) involved in the effects of morphine, selective opioid antagonists were microinjected into the lateral ventricle prior to morphine treatment (6 mg/kg, s.c.). CTOP (mu-selective antagonist, 5 micrograms/2 microliters) completely blocked the effects of morphine on all parameters measured, however, naltrindole (delta-selective antagonist, 2 micrograms/2 microliters) or nor-binaltorphimine (kappa-selective antagonist, 73.5 micrograms/2 microliters) failed to block the effects of morphine. Collectively, these results provide evidence that morphine acts primarily through central mu receptors to modulate peripheral blood lymphocyte proliferation responses. Further, the antinociception and blood lymphocyte effects show greater sensitivity to opioids than either natural killer cell cytolytic activity or activation of the HPA axis.