Neurokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception.
BACKGROUND
Neurokinins (e.g., substance P) contribute to pain transmission in the central nervous system, peripheral neurogenic inflammation, and leukocyte recruitment in inflammation. Leukocyte recruitment involves (1) up-regulation of adhesion molecule expression through neurokinin-1 (NK1) receptors on endothelial cells, (2) augmented chemokine production, or (3) chemotaxis through NK1 receptors on leukocytes. In inflammation, leukocytes can trigger endogenous antinociception through release of opioid peptides and activation of opioid receptors on peripheral sensory neurons. The authors hypothesized that NK1 receptor antagonists impair recruitment of opioid-containing leukocytes and stress-induced antinociception.


METHODS
Rats were treated intraperitoneally and intrathecally with peripherally restricted (SR140333) or blood-brain barrier-penetrating (L-733,060) NK1 receptor antagonists and were evaluated for paw pressure thresholds, numbers of infiltrating opioid-containing leukocytes and leukocyte subpopulations, expression of adhesion molecules, NK1 receptors, and chemokines 24-48 h after complete Freund adjuvant-induced hind paw inflammation.


RESULTS
Systemic and peripherally selective, but not intrathecal, NK1 receptor blockade reduced stress-induced antinociception (control: 177 +/- 9 g, L-733,060: 117 +/- 8 g, and control: 166 +/- 30 g, SR140333: 89 +/- 3 g; both P < 0.05, t test) without affecting baseline hyperalgesia. In parallel, local recruitment of opioid-containing leukocytes was decreased (L-733,060 and SR140333: 56.0 +/- 4.3 and 59.1 +/- 7.9% of control; both P < 0.05, t test). NK1 receptors were expressed on peripheral neurons, infiltrating leukocytes and endothelial cells. Peripheral NK1 receptor blockade did not alter endothelial expression of intercellular adhesion molecule-1 or local chemokine and cytokine production, but decreased polymorphonuclear cell and macrophage recruitment.


CONCLUSIONS
Endogenous inhibition of inflammatory pain is dependent on NK1 receptor-mediated recruitment of opioid-containing leukocytes.
Klinik für Anaesthesiologie m.S. operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Heike L
HL
Rittner
Christian
C
Lux
Dominika
D
Labuz
Shaaban A
SA
Mousa
Michael
M
Schäfer
Christoph
C
Stein
Alexander
A
Brack
D000818:Animals; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D018847:Opioid Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism
D009292:Narcotic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D018847:Opioid Peptides; D018040:Receptors, Neurokinin-1