Modulation of immune function by morphine: Implications for susceptibility to infection

The effect of opioids on the immune system is summarized in Table 1. It is clear that both acute and chronic morphine treatment affect innate and adaptive immunity. These effects will have immense therapeutic consequences. Morphine has been shown to mediate these effects by acting directly both on receptors present on the immune cells and on centrally mediated pathways. Molecular biological studies have shown that immune cells differentially express the mu opioid receptor. Whereas morphine has been shown to affect the development, differentiation, and function of immune cells, the intracellular pathways by which this multitude of effects are brought about have only recently been investigated. Modulation of the adenylyl cyclase pathway leading to the alteration of the MAP kinase pathway has been implicated in a number of studies as a plausible mechanism by which morphine modulates functions of immune cells. Activating signals from immune cells increase opioid receptor expression, and studies have shown that downstream signals of immune cells transactivate the expression of opioid receptor genes. The cross talk between mitogen activation and overexpression of opioid receptors and the observation that interaction of opioids with their receptors leads to immune suppression suggests that physiologically endogenous opioid peptides function as negative regulators of the immune system. It is also interesting to note that whereas chronic morphine treatment of neuronal cells results in receptor down-regulation and tolerance, in immune cells chronic morphine treatment results in mu opioid receptor overexpression and Th2 T-helper cell differentiation. Although there is general agreement that chronic morphine treatment compromises host defense, the exact mechanism appears to vary between animal models and dosing parameters. Thus, it is important to refine the existing animal model to closely match human conditions and to cross-validate these findings through carefully controlled human studies.