EVIDENCE FOR THE INVOLVEMENT OF THE CAUDAL REGION OF THE PERIAQUEDUCTAL GRAY IN A SUBSET OF MORPHINE-INDUCED ALTERATIONS OF IMMUNE STATUS

This study was directed at determining whether morphine's immunomodula tory effects are mediated through the periaqueductal gray (PAG). The i nitial study showed that microinjection of morphine (0.0, 0.4, 4.0, or 40.0 mu g/rat) into the lateral ventricle induces pronounced dose-dep endent reductions in lymphocyte proliferation to T- and B-cell mitogen s, natural killer cell cytotoxicity, and the production of interleukin -2 and interferon-gamma. In contrast, microinjection of morphine (0.0, 0.004, 0.04, 0.4, or 4.0 mu g/rat) into the caudal aspect of the PAG induced dose-dependent alterations in natural killer cell cytotoxicity , but had no effect on lymphocyte proliferation or cytokine production . These results indicate that opioid receptors in the FAG are involved in the regulation of natural killer cell activity, but are not associ ated with morphine's effects on proliferation or cytokine production. A subsequent study showed that the effect of morphine in the PAG is re stricted to the more caudal aspects of the PAG because microinjections of morphine into the rostral aspects do not result in any alteration of immune status. To determine that the activation of opioid receptors in the PAG is not only sufficient, but is required for morphine's eff ects on natural killer cell activity, N-methylnaltrexone was administe red into the PAG (0, 0.0001, 0.001, or 0.01 mu g/rat) before the syste mic administration of morphine (15 mg/kg), a dose that induces pronoun ced alterations of natural killer cell activity. The results showed th at the administration of N-methylnaltrexone directly into the PAG anta gonized morphine's effects on natural killer cell activity, which indi cate that activation of opioid receptors within the PAG are required f or morphine to alter natural killer cell activity, Collectively, this study showed that activation of opioid receptors within the more cauda l aspects of the PAG are required for morphine to induce alterations i n splenic natural killer cell activity. The results also suggest that other brain regions are responsible for morphine's effect on lymphocyt e proliferation and cytokine production.