Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain.
The chemokines use G protein-coupled receptors to regulate the migratory and proadhesive responses of leukocytes. Based on observations that G protein-coupled receptors undergo heterologous desensitization, we have examined the ability of chemokines to also influence the perception of pain by cross-desensitizing opioid G protein-coupled receptors function in vitro and in vivo. We find that the chemotactic activities of both mu- and delta-opioid receptors are desensitized following activation of the chemokine receptors CCR5, CCR2, CCR7, and CXCR4 but not of the CXCR1 or CXCR2 receptors. Furthermore, we also find that pretreatment with RANTES/CCL5, the ligand for CCR1, and CCR5 or SDF-1alpha/CXCL12, the ligand for CXCR4, followed by opioid administration into the periaqueductal gray matter of the brain results in an increased rat tail flick response to a painful stimulus. Because chemokine administration into the periaqueductal gray matter inhibits opioid-induced analgesia, we propose that the activation of proinflammatory chemokine receptors down-regulates the analgesic functions of opioid receptors, and this enhances the perception of pain at inflammatory sites.
Department of Microbiology and Immunology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Imre
I
Szabo
Xiao-Hong
XH
Chen
Li
L
Xin
Martin W
MW
Adler
O M Z
OM
Howard
Joost J
JJ
Oppenheim
Thomas J
TJ
Rogers
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism* / Q000494:pharmacology; D019742:Chemokines, CC / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000503:physiopathology*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000378:metabolism; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
D000701:Analgesics, Opioid; C515460:CCL19 protein, human; C515334:CCR2 protein, human; C515370:CCR7 protein, human; C515255:CXCL12 protein, human; C515461:Ccl19 protein, mouse; C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; C515371:Ccr7 protein, mouse; C515372:Ccr7 protein, rat; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016209:Interleukin-8; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020881:Enkephalin, D-Penicillamine (2,5)-