Characterization of NK1-receptors in guinea-pig ileum: Use of non-peptide NK1-receptor antagonists

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.

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Evidence for functional tachykinin NK1 receptors on human isolated small bronchi

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1996.271.5.l763 ◽

1996 ◽

Vol 271 (5) ◽

pp. L763-L767 ◽

Cited By ~ 3

Author(s):

E. Naline ◽

M. Molimard ◽

D. Regoli ◽

X. Emonds-Alt ◽

J. F. Bellamy ◽

...

Keyword(s):

Rank Order ◽

Intrinsic Activity ◽

Maximal Effect ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Response Curves ◽

Receptor Agonists ◽

Nk1 Receptors ◽

Nk2 Receptor ◽

Nk1 Receptor Antagonists

On human small isolated bronchi (diameter < 1 mm), but not on larger bronchi (diameter 3-5 mm), substance P (SP) and specific tachykinin SP-preferring neurokinin (NK1) receptor agonists inverted question mark[beta Ala4, Sar9, Met(O2)11]SP-(4-11), [Sar9, Met(O2)11]SP, [Arg6,Sar9,Met(O2)11]SP-(6-11), and septide; 10(-10) to 10(-6) M] produced a concentration-dependent contraction that occurred at low concentrations (pD2 values of 7.79-8.33) and was characterized by a low intrinsic activity [maximal effect (Emax) of 38-45% of Emax induced by 3 mM acetylcholine, in a noncumulative manner]. Comparison of cumulative and noncumulative concentration-response curves to SP and NK1 receptor agonists suggest rapid receptor desensitization. The SP (10(-8) M)-induced contraction was inhibited by tachykinin NK1 receptor antagonists (rank order of potency: SR-140333 > CP-96,345 > RP-67580) but not by the tachykinin NK2 receptor antagonist SR-48968. Indomethacin (10(-6) M) abolished the SP-induced contraction. Our results suggest that tachykinin NK1 receptors are present on human small bronchi and that their stimulation induces a prostanoid-dependent contraction. The small isolated bronchus is an interesting model of human tissue to test NK1 receptor antagonists.

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