Morphine activation of stress pathways alters peripheral immune cell signaling

Abstract

Morphine is routinely used as an analgesic for acute and chronic pain often in people at greater risk for infection, in spite of the fact that morphine suppresses immune function. Recent studies indicate that morphine alters antigen presenting gene expression including genes encoding for MHC-II. As alterations of antigen presentation directly affect immune cell activation, proliferation, and survival, both innate and acquired immune responses may be attenuated after morphine treatment or withdrawal.

Few studies have examined the effects of morphine on antigen presentation. Therefore, these studies sought to characterize the effect of morphine on MHC-II expression. Morphine (10 mg/kg, 2 hours) was found to significantly reduce basal and IL-4 induced MHC-II expression on circulating B lymphocytes. This effect appeared to be mediated through centrally located mu-opioid receptors as central injection of DAMGO mimicked the morphine-induced suppression of MHC-II while it was blocked by central pretreatment with naltrexone or CTOP. Since morphine activates the HPA axis, the role of corticosterone in mediating these effects was examined. Corticosterone decreased basal MHC-II expression on naïve leukocytes by 88% and completely prevented the IL-4 induction of MHC-II. As with morphine, stress-induced elevation of corticosterone also resulted in decreased MHC-II expression. Additionally, morphine-induced suppression of MHC-II was absent in adrenalectomized animals.

To determine the cellular consequences of exposure to elevated glucocorticoids in the context of morphine and/or stress, the effects of these exposures on cell cycle and apoptosis were evaluated in circulating mononuclear cells. Neither acute nor chronic morphine treatment increased leukocyte apoptosis. The effect of stress on chronic morphine treated leukocytes was mixed as restraint stress appeared anti-apoptotic while cold water stress increased leukocyte apoptosis. This increase in apoptosis coincided with an increase in proliferative phases of the cell cycle in leukocytes. Finally, withdrawal from morphine dramatically increased leukocyte apoptosis even seven days after withdrawal. These results demonstrate that morphine alters immune cells signaling capabilities through HPA dependent reductions in MHC-II expression. Furthermore, prolonged exposure to morphine produces alterations in cell signaling such that immune cells may be more susceptible to activation of apoptotic pathways in response to certain types of stress.