Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells.
Opioid-containing leukocytes can counteract inflammatory hyperalgesia. Under stress or after local injection of corticotropin releasing factor (CRF), opioid peptides are released from leukocytes, bind to opioid receptors on peripheral sensory neurons and mediate antinociception. Since polymorphonuclear cells (PMN) are the predominant opioid-containing leukocyte subpopulation in early inflammation, we hypothesized that PMN and their recruitment by chemokines are important for peripheral opioid-mediated antinociception at this stage. Rats were intraplantarly injected with complete Freund's adjuvant (CFA). Using flow cytometry, immunohistochemistry, and ELISA, leukocyte subpopulations, chemokine receptor (CXCR2) expression on opioid-containing leukocytes and the CXCR2 ligands keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant-2 (CINC-2) were quantified. Paw pressure threshold (PPT) was determined before and after intraplantar and subcutaneous injection of CRF with or without naloxone. PMN depletion was achieved by intravenous injection of an antiserum. Chemokines were blocked by intraplantar injection of anti-MIP-2 and/or anti-KC antiserum. We found that at 2 h post CFA (i) intraplantar but not subcutaneous injection of CRF produced dose-dependent and naloxone-reversible antinociception (P<0.05, ANOVA). (ii) Opioid-containing leukocytes in the paw and CRF-induced antinociception were reduced after PMN depletion (P<0.05, t-test). (iii) Opioid-containing leukocytes mostly expressed CXCR2. MIP-2 and KC, but not CINC-2 were detectable in inflamed but not in noninflamed tissue (P<0.05, ANOVA). (iv) Combined but not single blockade of MIP-2 and KC reduced the number of opioid-containing leukocytes and peripheral opioid-mediated antinociception (P<0.05, t-test; P>0.05, ANOVA). In summary, in early inflammation peripheral opioid-mediated antinociception is critically dependent on PMN and their recruitment by CXCR2 chemokines.
Brack
Alexander
A
Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
Rittner
Heike L
HL
Machelska
Halina
H
Leder
Kerstin
K
Mousa
Shaaban A
SA
Schäfer
Michael
M
Stein
Christoph
C
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D002465:Cell Movement / Q000502:physiology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000276:immunology / Q000502:physiology*; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D005620:Freund's Adjuvant; D005786:Gene Expression Regulation / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism*; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000150:complications / Q000628:therapy*; D009504:Neutrophils / Q000378:metabolism*; D010146:Pain / Q000209:etiology; D059408:Pain Management; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D023063:Receptors, Interleukin-8B / Q000378:metabolism
D000906:Antibodies; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; C513294:Cxcl3 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D009294:Narcotics; D023063:Receptors, Interleukin-8B; D009270:Naloxone; D005620:Freund's Adjuvant; D003346:Corticotropin-Releasing Hormone