OPIATES TRANSDEACTIVATE CHEMOKINE RECEPTORS - DELTA-OPIATE AND MU-OPIATE RECEPTOR-MEDIATED HETEROLOGOUS DESENSITIZATION

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 pert ussis toxin-sensitive manner. Metenkephalin, as well as morphine, inhi bited IL-8-induced chemotaxis of human neutrophils and macrophage infl ammatory protein (MIP)-1 alpha, regulated upon activation, normal T ex pressed and secreted RANTES), and monocyte chemoattractant protein 1, but not MIP-1 beta-induced chemotaxis of human monocytes. This inhibit ion of chemotaxis was mediated by delta and mu but not kappa G protein -coupled opiate receptors. Calcium nux induced by chemokines was unaff ected by met-enkephalin pretreatment. Unlike other opiate-induced chan ges in leukocyte function, the inhibition of chemotaxis was not mediat ed by nitric oxide. Opiates induced phosphorylation of the chemokine r eceptors CXCR1 and CXCR2, but neither induced internalization of chemo kine receptors nor perturbed chemokine binding. Thus, inhibition of ch emokine-induced chemotaxis by opiates is due to heterologous desensiti zation through phosphorylation of chemokine receptors. This may contri bute to the defects in host defense seen with opiate abuse and has imp ortant implications for immunomodulation induced by several endogenous neuropeptides which act through G protein-coupled receptors.