Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons.
Pain is one of the hallmarks of inflammation. Opioid receptors mediate antipain responses in both the peripheral nervous system and CNS. In the present study, pretreatment of CCR1: mu-opioid receptor/HEK293 cells with CCL3 (MIP-1alpha) induced internalization of mu-opioid receptors and severely impaired the mu-opioid receptor-mediated inhibition of cAMP accumulation. Immunohistochemical staining showed that CCR1 and mu-opioid receptors were coexpressed on small to medium diameter neurons in rat dorsal root ganglion. Analysis of ligand-induced calcium flux showed that both types of receptors were functional. Pretreatment of neurons with CCL3 exhibited an impaired [D-Ala(2),N-MePhe(4),Gly-o15]enkephalin-elicited calcium response, indicative of the heterologous desensitization of mu-opioid receptors. Other chemokines, such as CCL2, CCL5, and CXCL8, exhibited similar inhibitory effects. Our data indicate that proinflammatory chemokines are capable of desensitizing mu-opioid receptors on peripheral sensory neurons, providing a novel potential mechanism for peripheral inflammation-induced hyperalgesia.
Zhang
Ning
N
Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702, USA.
Rogers
Thomas J
TJ
Caterina
Michael
M
Oppenheim
Joost J
JJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D000242:Cyclic AMP / Q000096:biosynthesis; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects*; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D008297:Male; D011506:Proteins / Q000494:pharmacology; D051381:Rats; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000032:analysis; D017450:Receptors, Opioid, mu / Q000032:analysis / Q000187:drug effects*
C491766:Ccl2 protein, rat; C515302:Ccr1 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D011506:Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D000242:Cyclic AMP; D002118:Calcium