Morphine Suppresses MHC-II Expression on Circulating B Lymphocytes via Activation of the HPA

Abstract

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. Morphine suppresses immunity in both humans and animal models, with studies demonstrating that a single morphine injection induces lymphopenia and alters normal immune function (e.g., lymphocyte proliferation, antibody production, natural killer cell activity) (Bayer et al. 1990;Lockwood et al. 1994). To better understand the effect of morphine on immunity, previous studies conducted by our group examined morphineinduced gene expression changes in circulating rat leukocytes. Results indicated that morphine altered the expression of several genes related to antigen presentation, specifically genes coding for proteins associated with the major histocompatibility complex, class II (MHC-II) (Beagles et al. 2004). MHC-II molecules are important regulators of both immune cell development and function. Studies of MHC-II knockout mice demonstrate that the loss of MHC-II produces a marked reduction in CD4 + T-lymphocyte number (Madsen et al. 1999). In addition, MHC-II is a key molecule involved in immune cell development, activation, and s...

Opioid Drug Abuse and Modulation of Immune Function: Consequences in the Susceptibility to Opportunistic Infections

“…Effects of acute morphine treatment are comparable to morphine withdrawal, while chronic morphine treatment seems to have opposite results. These differences will be discussed in detail in section 7 of this review (Flores et al, 1995; Fecho and Lysle, 1999; Donahoe et al, 2001; Mellon et al, 2001; Wang et al, 2001; Qian et al, 2005; Nugent et al, 2011). …”

“…The immunomodulatory effects of morphine on macrophages, monocytes and DCs have been well documented (Wang et al, 2008a), mostly in the context of innate immunity and have been covered in the previous section of this review. In terms of the essential function of the APCs in T cell activation, recent information highlights the role of B cells and acute morphine mediated impaired antigen presentation in these cells (Beagles et al, 2004; Nugent et al, 2011). This becomes important, since a coordinated antigen presentation by the B cells and DCs is an absolute necessity for optimal CD4 + T cell activation (Kleindienst and Brocker, 2005).…”

“…It has been shown that as little as 10 mg/kg b.w. morphine treatment reduced the MHC-II expression on the circulating B cells by almost 33%, which cannot be rescued upon IL-4 administration (Nugent et al, 2011). However, it remains an open argument whether morphine is directly modulating the APCs or indirectly by mediating effects on the central HPA axis.…”

“…However, it remains an open argument whether morphine is directly modulating the APCs or indirectly by mediating effects on the central HPA axis. Some studies implicate a central HPA axis mediated changes in antigen presentation, where direct corticosterone treatment was able to reduce MHC-II expression on APCs, irreversible upon stimulation with IL-4 (Schwab et al, 2005; Nugent et al, 2011). In summary, while the effects of morphine on antigen presentation is clear (Wang et al, 2008b), more work is needed to delineate the exact mechanism involved, and to identify the primary target of morphine in these cells or in the central HPA and/or the sympathetic nervous system (if any).…”

A Growth Factor Attenuates HIV-1 Tat and Morphine Induced Damage to Human Neurons: Implication in HIV/AIDS-Drug Abuse Cases

“…Immunosuppression by opiates, particularly morphine, has been very well studied and is mediated via alterations in peripheral lymphocyte activity [13] and suppression of major histocompatibility complex-II (MHC-II) expression [14]. Morphine renders the brain more susceptible to HIV infection by enhancing macrophage infiltration by inducing MCP-1 expression from activated astrocytes and resident microglia [15].…”