Morphine suppresses MHC-II expression on circulating B lymphocytes via activation of the HPA

Morphine has been shown to alter gene expression of the major histocompatibility complex, class II (MHC-II) in circulating rat immunocytes. Here, we demonstrate that a single morphine injection (10 mg/kg) reduces basal MHC-II protein expression on circulating B lymphocytes by 33%, while also impairing the ability of B lymphocytes to increase MHC-II upon interleukin-4 induction. As these data implicate opioids in the regulation of antigen presentation, studies were undertaken to examine the potential mechanisms through which morphine exerts this suppressive effect. Central injection studies utilized Tyr-D-Ala-Gly-(me) Phe-Gly-ol (DAMGO), an opioid receptor agonist, which mimicked morphine's effect on MHC-II, while D-Phe-Cys_Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) pretreatment, prior to morphine, blocked the suppression of MHC-II. As central opioid receptor activation results in the activation of the hypothalamic-pituitary-adrenal axis, thereby, signaling increased circulating corticosterone levels, we examined whether MHC-II expression was suppressed after incubation with corticosterone at concentrations similar to those observed after morphine. Interestingly, corticosterone dramatically decreased basal MHC-II (88%) expression while completely preventing the induction of MHC-II. Additionally, MHC-II suppression was absent in morphine-treated adrenalectomized animals. Since prolonged morphine exposure has previously been shown to result in tolerance to both the steroidogenic and immunosuppressive effects of morphine, the effect of prolonged morphine exposure on MHC-II was also examined. Interestingly, MHC-II expression is no longer suppressed after chronic morphine, while morphine withdrawal results in both a renewed increase in circulating corticosterone levels and a renewed suppression of MHC-II in previously tolerant animals. Taken together, these data strongly implicate corticosterone in mediating the suppressive effects of morphine on circulating B-lymphocyte MHC-II expression.