Opiates transdeactivate chemokine receptors: delta 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 pertussis toxin-sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8-induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1beta-induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by delta and micro but not kappa 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.
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, Science Applications International Corp. Frederick, Frederick, Maryland 21702, USA. grimm@mail.ncifcrf.gov
M C
MC
Grimm
A
A
Ben-Baruch
D D
DD
Taub
O M
OM
Howard
J H
JH
Resau
J M
JM
Wang
H
H
Ali
R
R
Richardson
R
R
Snyderman
J J
JJ
Oppenheim
D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000166:cytology* / Q000502:physiology*; D009294:Narcotics / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D017465:Receptors, Opioid, delta / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D009294:Narcotics; D019707:Receptors, Chemokine; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu