title: Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons.
abstract: 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.
authors.affiliation: Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
authors.forename: Michael
authors.initials: M
authors.lastname: Caterina
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
mesh_terms: 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*
chemical_list: 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