J. Exp. Med., Volume 188, Number 2, July 20, 1998 317-325

Opiates Transdeactivate Chemokine Receptors:  and µ Opiate Receptor-mediated Heterologous Desensitization

By M.C. Grimm,^* A. Ben-Baruch,^* D.D. Taub, O.M.Z. Howard, J.H. Resau,^§ J.M. Wang, H. Ali,^¶ R. Richardson,^¶ R. Snyderman,^¶ and J.J. Oppenheim^*

From the ^* Laboratory of Molecular Immunoregulation, Division of Basic Sciences, and the  Intramural Research Support Program, Science Applications International Corp. Frederick, Frederick, Maryland 21702; the ^§ ABL-Basic Research Program, National Cancer Institute - Frederick Cancer Research and Development Center, Frederick, Maryland 21702; the  Laboratory of Immunology, National Institute on Aging, Baltimore, Maryland 21224; and the ^¶ Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

An intact chemotactic response is vital for leukocyte trafficking and host defense. Opiates are known to exert a number of immunomodulating effects in vitro and in vivo, and we sought to determine whether they were capable of inhibiting chemokine-induced directional migration of human leukocytes, and if so, to ascertain the mechanism involved. The endogenous opioid met-enkephalin induced monocyte chemotaxis in a pertussis toxin-sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8-induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1-induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by  and µ but not  G protein-coupled opiate receptors. Calcium flux induced by chemokines was unaffected by met-enkephalin pretreatment. Unlike other opiate-induced changes in leukocyte function, the inhibition of chemotaxis was not mediated by nitric oxide. Opiates induced phosphorylation of the chemokine receptors CXCR1 and CXCR2, but neither induced internalization of chemokine receptors nor perturbed chemokine binding. Thus, inhibition of chemokine-induced chemotaxis by opiates is due to heterologous desensitization through phosphorylation of chemokine receptors. This may contribute to the defects in host defense seen with opiate abuse and has important implications for immunomodulation induced by several endogenous neuropeptides which act through G protein-coupled receptors.

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