The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus, the house musk shrew

Abstract

1. In SUNCUS: murinus the ultrapotent capsaicin analogue resiniferatoxin (RTX) induced an emetic response in the dose range 1 - 1000 microg kg(-1), s.c. The latency was inversely related to dose and ranged from 41.2+/-4.4 min. (1 microg kg(-1), s.c.) to 2.7+/-0.6 min. (1000 microg kg(-1), s.c.). 2. The emetic response to RTX (10 or 100 microg kg(-1), s.c.) was blocked or markedly reduced by pre-treatment with RTX (100 microg kg(-1), s.c.), 8-OH-DPAT (100 microg kg(-1), s.c.), morphine (2 mg kg(-1), s.c.), neonatal capsaicin (100 mg kg(-1), s.c.) and the NK(1) receptor antagonist CP-99,994 (10 - 20 mg kg(-1), s.c.) but not by the 5-HT(3) receptor antagonist tropisetron (200 microg kg(-1), s.c.). 3. RTX (100 microg kg(-1), s.c.) induced c-fos-like immunoreactivity in the area postrema and parts of the nucleus tractus solitarius. This pattern is consistent with the proposal that the emetic effect is mediated via one or both of these structures and an involvement of substance P is discussed. 4. RTX (10 and 100 microg kg(-1), s.c.) had broad-spectrum antiemetic effects in Suncus as indicated by its ability to block or markedly reduce the emetic response to motion (1 Hz, 4 cm lateral, 10 min.), cisplatin (20 mg kg(-1), i.p.), intragastric copper sulphate (40 mg kg(-1), p.o.), nicotine (10 mg kg(-1), s.c.) and RTX (100 microg kg(-1), s.c.) itself. 5. It is proposed that the site of the anti-emetic effect is in the nucleus tractus solitarius and mechanisms involving the modulation of substance P release are discussed. 6. The general utility of SUNCUS: for investigations of vanilloid receptors is reviewed in the light of the exquisite sensitivity of the emetic reflex in this species to resiniferatoxin.

Figure 1

The relationship between the log-dose of resiniferatoxin (RTX) given subcutaneously to groups of Suncus and the mean±s.e.mean latency and number of emetic episodes induced over a 1-h observation period. The number of animals responding over the number tested is shown for each dose. For the dose of 1000 μg kg⁻¹ the value for latency is calculated from the three animals with an early response (see text for details).

Figure 2

The profile of the emetic response to groups of Suncus given either 100 or 500 μg kg⁻¹ s.c. The number (mean±s.e.mean) of episodes is plotted in 5 min time bins and the number of animals responding over those tested is shown for each time bin.

Figure 3

Photomicrographs of a representative transverse section of the caudal dorsal brainstem of Suncus showing fos-like immunoreactivity (dark stained cells) in one animal given RTX (100 μg kg⁻¹ s.c. upper panel) and in another given its vehicle (lower panel). Note the intense fos-like immunoreactivity bilaterally in the nucleus tractus solitarius (NTS) and to a lesser extent in the body of area postrema (AP) in the RTX-treated animal. Fos-like immunoreactivity was noted in the dorsal motor vagal nucleus (DMX) but it was less dense than in the NTS.