Selectins and integrins but not platelet-endothelial cell adhesion molecule-1 regulate opioid inhibition of inflammatory pain.
1. Control of inflammatory pain can result from activation of opioid receptors on peripheral sensory nerves by opioid peptides secreted from leukocytes in response to stress (e.g. experimental swim stress or surgery). The extravasation of immunocytes to injured tissues involves rolling, adhesion and transmigration through the vessel wall, orchestrated by various adhesion molecules. 2. Here we evaluate the relative contribution of selectins, integrins alpha(4) and beta(2), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) to the opioid-mediated inhibition of inflammatory pain. 3. We use flow cytometry, double immunofluorescence and nociceptive (paw pressure) testing in rats with unilateral hind paw inflammation induced by complete Freund's adjuvant. 4. In inflamed tissue, 43-58% of hematopoietic cells (CD45(+)) expressed opioid peptides. L-selectin and beta(2) were coexpressed by 7 and 98% of opioid-containing leukocytes, respectively. Alpha(4) integrin was expressed in low levels by the majority of leukocytes. Opioid-containing cells, vascular P- and E-selectin and PECAM-1 were simultaneously upregulated. 5. Swim stress produced potent opioid-mediated antinociception in inflamed tissue, unaffected by blockade of PECAM-1. However, blockade of L- and P-selectins by fucoidin, or of alpha(4) and beta(2) by monoclonal antibodies completely abolished peripheral stress-induced antinociception. This coincided with a 40% decrease in the migration of opioid-containing leukocytes to inflamed tissue. 6. These findings establish selectins and integrins alpha(4) and beta(2), but not PECAM-1, as important molecules involved in stress-induced opioid-mediated antinociception in inflammation. They point to a cautious use of anti-inflammatory treatments applying anti-selectin, anti-alpha(4) and anti-beta(2) strategies because they may impair intrinsic pain inhibition.
Machelska
Halina
H
Klinik fur Anaesthesiologie und operative Intensivmedizin, Charite-Universitatsmedizin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. halina.machelska@charite.de
Brack
Alexander
A
Mousa
Shaaban A
SA
Schopohl
Julia K
JK
Rittner
Heike L
HL
Schäfer
Michael
M
Stein
Christoph
C
D000818:Animals; D001169:Arthritis, Experimental; D001792:Blood Platelets / Q000737:chemistry / Q000502:physiology; D018821:CD18 Antigens / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004723:Endorphins / Q000502:physiology; D042783:Endothelial Cells / Q000737:chemistry / Q000502:physiology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D005620:Freund's Adjuvant / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D005858:Germany; D007249:Inflammation / Q000150:complications / Q000517:prevention & control*; D039441:Integrin alpha4 / Q000187:drug effects / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008297:Male; D010146:Pain / Q000150:complications / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019087:Selectins / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
D018821:CD18 Antigens; D004723:Endorphins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011134:Polysaccharides; D019087:Selectins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D005620:Freund's Adjuvant; C007789:fucoidan; D017493:Leukocyte Common Antigens