Opioid mediated effects on the immune system: sympathetic nervous system involvement

Abstract

Opioids have been hypothesized to suppress parameters of immune function by acting within the central nervous system to increase the activity of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system. Production of catecholamines and adrenocorticoids have been demonstrated to be responsible for many of the observed immunomodulatory effects which occur following opioid administration. In general, the sympathetic nervous system has been shown to play a role in regulating lymphocyte proliferation and natural killer cell activity as well as several other parameters of immune function. Here, we will focus primarily on the role of the sympathetic nervous system in modulating opioid induced immunosuppression. The role of the hypothalamic–pituitary–adrenal axis is reviewed elsewhere in this issue.

Introduction

Drug abuse is a public health problem contributing to increased susceptibility to infectious disease, including possibly, the increased incidence of HIV seropositivity, and cancer. Clinical observations first suggested that opiate addicts have an increased susceptibility to infections (Hussey, 1950; Louria et al., 1967; Sapira, 1968) findings subsequently shown to be related to deficits in immune function (Brown et al., 1974). Pre-clinical studies have demonstrated that opioids lead to decreased survival (Lewis et al., 1983) and increased metastases (Yeager and Colacchio, 1991) in tumor-bearing animals, as well as increase the susceptibility of animals to bacterial and viral infections (Tubaro et al., 1983; Molitor et al., 1993; Watson and Nguyen, 1990).

In vivo injection of opioids alters a number of immune parameters which increase susceptibility to disease (for review see Weber and Pert, 1984; Carr et al., 1996; Gomez-Flores and Weber, 1998a, Gomez-Flores and Weber, 1998b). Opioids such as morphine have been reported to suppress B (intracerebroventricular (ICV) injection, Lysle et al., 1996) and T-cell proliferation (subcutaneous (sc) injection, Lysle et al., 1993; Bayer et al., 1995; Flores et al., 1996; ICV injection, Lysle et al., 1996; periaqueductal gray matter (PAG) injection, Suo and Weber, 1998a) in rats. Administration of morphine has also been reported to suppress a variety of functions including murine T-cell mediated cytotoxicity (sc injection, Carr and Carpenter, 1995), production of rat (sc injection, Fecho et al., 1996b) or murine (sc injection, Scott and Carr, 1996) interferon-γ, and phagocytosis of Candida albicans by murine (sc injection, Rojavin et al., 1993), rat (PAG injection, Gomez-Flores and Weber, 1998a), or human (sc injection, Tubaro et al., 1987) macrophages. Additional studies have demonstrated opioid induced suppression of splenic natural killer (NK)-cell cytotoxic activity in rats (sc injection, Lysle et al., 1996; Fecho et al., 1996b; PAG injection, Weber and Pert, 1989, Lysle et al., 1996; ICV injection, Lysle et al., 1996), mice (sc injection, Scott and Carr, 1996; Carr et al., 1994a), Rhesus monkeys (sc injection, Carr and France, 1993a) and humans (Yeager et al., 1995; Provinciali et al., 1996), including parenteral heroin users, but interestingly, NK cell activity is not suppressed in methadone maintenance patients (Novick et al., 1989). In addition, suppression of NK cell activity is associated with increased mortality from Friend virus (Starec et al., 1991) and Toxoplasma gondii (Chao et al., 1990) infections.

Morphine-mediated impairment of immunity appears to be regulated by μ (Band et al., 1992) opioid-selective receptors on cells of the central nervous system (CNS). Peripheral administration of morphine may interact directly with opioid receptors on cells of the immune system (Makman, 1994; Carr et al., 1996) or on receptors within the CNS. However, there is not clear evidence for the direct interaction of morphine with lymphocyte, NK-cell, or macrophage opioid receptors in vivo to produce immunosuppression.

Intracerebroventricular (Shavit et al., 1986) and central periaqueductal gray (PAG) matter (Weber and Pert, 1989) administration of morphine triggers CNS opioid receptors to induce immunosuppression peripherally. These results have been confirmed and extended through the utilization of morphine and naltrexone derivatives that are unable to cross the blood–brain barrier. A derivative of the opioid receptor antagonist naltrexone, N-methylnaltrexone, which does not readily enter the CNS when injected peripherally, does not antagonize the immunosuppressive effects of morphine (Shavit et al., 1986; Fecho et al., 1996b). However, when N-methylnaltrexone is administered intracerebralventricularly (icv), it prevents most of the immunosuppressive effects of morphine that it was unable to prevent when given subcutaneously (sc). Similar studies have been carried out with a derivative of morphine, N-methylmorphine, which like N-methylnaltrexone does not readily cross the blood–brain barrier. N-methylmorphine, injected into the peritoneum, is unable to mimic the immunosuppressive effects of morphine (Shavit et al., 1986; Hernandez et al., 1993). However, when injected into the third ventricle of the brain, both N-methylmorphine and morphine exhibit nearly identical immunosuppressive responses. See Table 1.

The site of morphine's immunosuppressive action within the CNS has been precisely localized to the periaqueductal gray matter of the mesencephalon (Weber and Pert, 1989; Weber and Pert, 1998). In addition, electrical stimulation of the ventral/caudal PAG, but not stimulation of other more rostral PAG regions causes suppression of NK cell activity (Weber and Pert, 1991). It has also been hypothesized that endogenous opioid action in this brain region may have some relevance for understanding the ability of certain forms of stress to produce changes in the immune system through opioid-dependent mechanisms (Weber and Pert, 1989).

The centrally mediated action of morphine on the immune system although primarily mediated through the PAG, does involve other brain regions as well (Weber and Pert, 1998). Microinjection of morphine into the anterior hypothalamus leads to a 50% reduction in blood lymphocyte proliferation, without analgesia (Hernandez et al., 1993). However, microinjection into the third ventricle leads to a decrease in blood lymphocyte proliferation, along with analgesia. The precise mechanisms underlying the ability of morphine injections in the PAG to alter NK cell activities, of microinjection of morphine into the anterior hypothalamus to decrease lymphocyte proliferation or action in other brain regions to alter parameters of immunocompetence are not entirely clear. CNS signals to the immune system are relayed primarily through the hypothalamic–pituitary–adrenal axis (HPA) and/or via sympathetic innervation of lymphoid organs. Thus, enhanced opioid activity in the PAG could be translated into effects on blood lymphocyte proliferation, splenic and thymic lymphocyte proliferation, and NK cell activity either through hypothalamic efferents and activation of the HPA axis, or increases in peripheral sympathetic output (Weber and Pert, 1989).

The activation of the HPA axis elicits the production of adrenocorticotropin hormone from the pituitary which in turn elicits the release of the glucocorticoids which either suppress (Freier and Fuchs, 1994) or have no effect (Flores et al., 1994) on immune functions. It appears that chronic morphine treatment induces immunosuppression through glucocorticoids (Bryant et al., 1991), whereas the immunosuppressive effects of acute morphine administration appear to be glucocorticoid independent (Flores et al., 1996). Alternatively, the activation of the SNS by morphine through innervation of primary and secondary lymphoid organs (Felten et al., 1985), elicits the release of catecholamines (Conway et al., 1983), which have been demonstrated to suppress lymphocyte (Flores et al., 1996b), NK-cell (Katafuchi et al., 1993), and macrophage (Spengler et al., 1994) functions.

Investigations into the involvement of the HPA axis and glucocorticoids in the suppression of lymphoproliferation and NK cell activity in our lab (Suo and Weber, 1998b) have demonstrated that although glucocorticoid and ACTH levels increase temporally following the administration of morphine, prior administration of RU486, an antagonist to the glucocorticoid receptor, does not prevent suppression of lymphocyte proliferation or NK cell activity. In addition, the effects of opioids on lymphoproliferation and NK cell activity have been demonstrated to be dependent upon the lymphoid compartment from which the cells were derived (Bayer et al., 1990a). This would seem to suggest that glucocorticoids or other systemically released substances do not play a primary role in mediating suppression of lymphocyte proliferation and NK cell activity.