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Effect of the tachykinin NK 1 receptor antagonists, RP 67580 and SR 140333, on electrically‐evoked substance P release from rat spinal cord
Author(s) -
Malcangio Marzia,
Bowery Norman G.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17037.x
Subject(s) - substance p , tachykinin receptor , endocrinology , medicine , stimulation , receptor , neuropeptide , basal (medicine) , agonist , chemistry , biology , insulin
1 The effects of the non‐peptide tachykinin NK 1 receptor antagonists, RP 67580, SR 140333, CP‐96,345 and CP‐99,994 have been investigated on electrically‐evoked release of substance P‐like immunoreactivity (SP‐LI) from rat spinal cord slices. 2 RP 67580 (10 n m ) and SR 140333 (1 n m ), perfused 5 min prior to and during 8 min stimulation of the dorsal roots (20 V, 0.5 ms, 1 Hz), significantly enhanced SP‐LI release by 213 ± 43 ( n = 8) and 203 ± 31 ( n = 5) % of control evoked release (187 ± 16% of basal outflow, n = 22) respectively. Neither compound modified basal outflow of SP‐LI (15.3 ± 2.5 fmol/8 ml, n = 10). 3 RP 67580 (10 n m ) did not modify electrically‐evoked release of calcitonin gene‐related peptide‐LI from rat spinal cord slices. 4 CP‐96,345 (10 n m ) and CP‐99,994 (1 and 10 n m ) did not alter electrically‐evoked SP‐LI release; however, they both inhibited release at 1 μ m . Inhibition was also induced by 1 μ m RP 67580 but not 1 μ m SR 140333. 5 The effect of the NK 1 receptor agonists, [Sar 9 Met (O 2 ) 11 ]SP and [Sar 9 ]SP, could not be tested on SP‐LI release due to interference with the substance P radioimmunoassay (RIA). The other NK 1 receptor agonists used, GR 73632, [Pro 9 ]SP and septide, which did not interfere with the RIA, increased SP‐LI basal outflow by 1807 ± 713% ( n = 3), 1259 ± 160% ( n = 3) and 620 ± 69% ( n = 3) at 10 n m , 1 n m and 1 μ m , respectively. At the same concentrations, the three agonists also enhanced electrically‐evoked SP‐LI release by 204 ± 38% ( n = 6), 753 ± 40% ( n = 3) and 504 ± 97% ( n = 3), respectively. The GR 73632 (10 n m )‐induced increase in electrically‐evoked SP‐LI release, was not prevented by SR 140333 (100 n m ). None of the agonists inhibited SP‐LI release at lower concentrations (0.1 n m GR 73632; 0.01 and 0.1 n m [Pro 9 ]SP and 1–100 n m septide). 6 NKA and NKB, at concentrations up to 10 n m which did not interfere with the RIA, did not modify electrically‐evoked release of SP‐LI. 7 The ability of NK 1 receptor antagonists to enhance electrically‐evoked SP‐LI release supports the concept of an NK 1 autoreceptor control mechanism at substance P nerve terminals within the dorsal horn of the rat spinal cord.