Altered T-cell responsiveness in morphine "tolerant" rats: evidence for a potential role of the paraventricular nucleus of the hypothalamus.

Abstract

The acute administration of morphine produces significant alterations in several parameters of the immune system including lymphocyte proliferation responses, natural killer cell cytolytic activity, antibody production and macrophage function. Our laboratory has examined the effects of acute morphine on blood lymphocyte proliferation to the polyclonal mitogen concanavalin A (ConA) in the male Sprague-Dawley rat. These studies demonstrated that the acute suppressive effect of morphine on this in vitro measure of lymphocyte function is mediated by central opioid receptors, predominantly via the of opioid receptors. Mechanistic studies suggested that the effect of morphine on the blood lymphocyte proliferation response is largely independent of either pituitary or adrenal-derived factors. However, additional experiments implicated a role for the autonomic ganglia in the effects of acute morphine since the blockade of peripheral nicotinic receptors was found to completely antagonize the acute effect of morphine on this parameter. Further, the stimulation of peripheral nicotinic receptors with nicotine and epibatidine, a selective nicotinic receptor agonist, mimicked the effects of morphine on immune cells. It was concluded from these experiments that the acute effects of morphine on the blood lymphocyte proliferation response were mediated primarily through indirect stimulation of peripheral autonomic neurons. Studies examining the effects of chronic morphine administration have also demonstrated significant alterations in the same parameters of the immune system, including, lymphocyte proliferation, antibody production, natural killer cell cytolytic activity and macrophage function. However, in contrast to the primary mechanism mediating the effect of acute administration of morphine, the effect of chronic morphine on many of these parameters appears to be largely attributed to the prolonged elevations in glucocorticoids associated with chronic morphine treatment. Our laboratory has demonstrated that an apparent tolerance to the suppressive effect of morphine treatment on blood lymphocyte proliferation can be induced via an injection protocol