Effect of the tachykinin NK1 receptor antagonists, RP 67580 and SR 140333, on electrically-evoked substance P release from rat spinal cord.

1. The effects of the non-peptide tachykinin NK1 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 nM) and SR 140333 (1 nM), 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 nM) did not modify electrically-evoked release of calcitonin gene-related peptide-LI from rat spinal cord slices. 4. CP-96,345 (10 nM) and CP-99,994 (1 and 10 nM) did not alter electrically-evoked SP-LI release; however, they both inhibited release at 1 microM. Inhibition was also induced by 1 microM RP 67580 but not 1 microM SR 140333. 5. The effect of the NK1 receptor agonists, [Sar9 Met (O2)11]SP and [Sar9]SP, could not be tested on SP-LI release due to interference with the substance P radioimmunoassay (RIA). The other NK1 receptor agonists used, GR 73632, [Pro9]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 nM, 1 nM and 1 microM, 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 nM)-induced increase in electrically-evoked SP-LI release, was not prevented by SR140333 (100 nM). None of the agonists inhibited SP-LI release at lower concentrations (0.1 nM GR73632; 0.01 and 0.1 nM [Pro9]SP and 1-100 nM septide).6 NKA and NKB, at concentrations up to 10 nM which did not interfere with the RIA, did not modify electrically-evoked release of SP-LI.7 The ability of NKI receptor antagonists to enhance electrically-evoked SP-LI release supports the concept of an NK1 autoreceptor control mechanism at substance P nerve terminals within the dorsal horn of the rat spinal cord.