Review
Opioids, opioid receptors, and the immune response

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Abstract

It is now clear that opioid receptors participate in the function of the cells of the immune system, and evidence suggests that opioids modulate both innate and acquired immune responses. We review literature here which establishes that μ-, κ-, and δ-opioid compounds alter resistance to a variety of infectious agents, including the Human Immunodeficiency Virus (HIV). The nature of the immunomodulatory activity of the opioids has been the subject of a great deal of research over the last ten years. There is increasing evidence that effects of opioids on the immune response are mediated at several levels. Modulation of the inflammatory response appears to be a target of these compounds, including effects on phagocytic activity, as well as the response of cells to various chemoattractant molecules. Moreover, findings from several laboratories have demonstrated the impact of opioid treatment on antibody responses, and the molecular basis for this effect is likely due, at least in part, to the modulation of both cytokine and cytokine receptor expression. Future research should provide a clearer understanding of the cellular and molecular targets of opioid action within the immune system.

Introduction

There is a rapidly growing literature which has described a broad range of effects of opioid compounds on the function of cells of the immune system. It is clear that the immunomodulatory activity of opioids is likely to be due to a complex interplay of direct and indirect influences. In the whole animal, opioid modulation of the immune response is mediated, in part, directly through the interaction with opioid receptors expressed by one or more populations of immune cells. In addition, the influence of the opioids on the immune response in vivo is likely to be also the result of the participation of both the central nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. The results of studies carried out in the whole animal must be evaluated with the understanding that the brain, adrenal, and multiple sub-populations of immune cells may each play a role in the final outcome. This review will concentrate largely on the direct interaction of opioids with the cells of the immune system.

Section snippets

Pharmacological characterization of the leukocyte receptors

Pharmacological evidence has been reported which demonstrates the presence of μ-, κ-, and δ-opioid receptors, as well as non-classical opioid-like receptors, on cells of the immune system. Mehrishi and Mills (1983) reported naloxone binding to human lymphocytes and platelets, and this binding was found to be both specific and sensitive to competition with morphine. Studies carried out with human polymorphonuclear leukocytes have shown the presence of a stereospecific binding site for naloxone (

Molecular characterization of the leukocyte opioid receptors

Each of the major opioid receptor classes have now been cloned from neuronal cells and fully sequenced. These proteins are seven transmembrane receptors and share homology with the somatostatin receptor (Reisine and Bell, 1993). Analysis of the δ-opioid (Evans et al., 1992; Kieffer et al., 1992), κ-opioid (Li et al., 1993; Minami et al., 1993; Nishi et al., 1993; Yasuda et al., 1993; Zhu et al., 1995) and μ-opioid (Chen et al., 1993) sequences show a high degree of amino acid homology among the

Phagocytic cell function

The capacity of both peritoneal macrophages and neutrophils to phagocytose the pathogenic yeast Candida albicans is inhibited following in vivo administration of morphine (Tubaro et al., 1983, Rojavin et al., 1993, Pacifici et al., 1993). Studies reported by Rojavin et al. (1993) with non-elicited macrophages suggest that the inhibitory activity of morphine is blocked by the administration of the opioid antagonist naltrexone. This is in contrast to the results obtained by Tubaro et al. (1983)

Effect of opioids on hematopoietic cell development

It is well established that morphine administration in vivo results in atrophy of both the thymus and the spleen (Bryant et al., 1987; Arora et al., 1990; Sei et al., 1991; Bussiere et al., 1992b; Freier and Fuchs, 1993; Fuchs and Pruett, 1993; Hilburger et al., 1997a). Several groups of investigators have found that implantation of morphine pellets subcutaneously in mice induces a rapid and profound hypoplasia (up to 70–80% reduction in thymus weight) that is sustained for approximately 3

Opioids and resistance to infectious disease

It has long been appreciated that intravenous drug abusers have a greater incidence of infection than nonabusers (Hussey and Katz, 1950; Louria et al., 1967). The correlation of intravenous drug abuse and HIV infection is well established (Center for Disease Control, 1996). The extent of increased infection with other organisms may not be generally appreciated. Drug abusers are reported to have a markedly increased prevalence of viral hepatitis A, B, and C, bacterial pneumonias, tuberculosis,

Uncited references

Van Den Bergh et al., 1994 and Carr, 1991

Acknowledgements

This work was supported by grants DA 06650, DA 11134, DA 11130, F31 DA 05894, and T32 DA07237 from NIDA.

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