Respiratory action of capsaicin microinjected into the nucleus of the solitary tract: involvement of vanilloid and tachykinin receptors

Abstract

1. The respiratory response to microinjection of capsaicin into the commissural nucleus of the solitary tract (cNTS) of urethane-anaesthetized rats was investigated in the absence and presence of the competitive vanilloid (capsaicin) antagonist, capsazepine, and selective tachykinin NK1, NK2 and NK3 antagonists (RP 67580, SR 48968 and SR 142801, respectively). 2. Microinjection of capsaicin reduced respiratory frequency but not tidal volume (VT), leading to an overall reduction in minute ventilation (VE). The effect was dose-dependent between 0.5 and 2 nmol capsaicin. Doses greater than 2 nmol produced apnoea. Tachyphylaxis was observed following repeated injection of capsaicin (1 nmol, 30 min apart). 3. Capsazepine (1 nmol) had no effect on frequency or VT when injected alone but completely blocked the respiratory response to capsaicin (1 nmol). 4. RP 67580 (1 but not 5 nmol) alone depressed frequency and VT slightly. Moreover, RP 67580 appeared to potentiate the bradypnoeic effect of capsaicin. In contrast, SR 48968 and SR 142801 (1 and 5 nmol) alone had no significant effect on respiration. However, both agents significantly attenuated the reduction in frequency produced by capsaicin. 5. In conclusion, microinjection of capsaicin into the cNTS decreases overall ventilation, primarily by reducing frequency. The action of capsaicin appears from the data to be mediated by vanilloid receptors since it is blocked by the competitive vanilloid antagonist capsazepine and is subject to tachyphylaxis. However, since NK2 (SR 48968) and NK3 (SR 142801) receptor antagonists block the actions of capsaicin, we propose that capsaicin acts also by releasing tachykinins from central afferent terminals in the cNTS.

Figure 1

Representative chart tracings which show respiratory movements before (control) and 10 min after microinjection of 500 nl vehicle (a) and 1 nmol capsaicin (b) into the commissural nucleus of the solitary tract of urethane-anaesthetized, spontaneously breathing rats. The bottom panels (c) show the effect of 3 nmol capsaicin, which produced irreversible apnoea (arrow) 2 min after injection.

Figure 2

(a) Respiratory frequency (f), (b) tidal volume (VT) and (c) minute ventilation (V̇E) in rats following microinjection of capsaicin (0.5–2.0 nmol) or vehicle (25% ethanol in normal saline) into the commissural nucleus of the solitary tract of urethane-anaesthetized, spontaneously breathing rats. Values are the mean of four to eight animals and vertical bars show s.e.mean.

Figure 3

(a) Respiratory frequency (f), (b) tidal volume (VT) and (c) minute ventilation (V̇E) in rats following repeated injection of capsaicin (×3, 1 nmol, 30 min apart) into the commissural nucleus of the solitary tract of urethane-anaesthetized, spontaneously breathing rats. Values are the mean of four animals and vertical bars show s.e.mean. ^*P<0.05 versus injection one (ANOVA followed by Fisher's LSD test).

Figure 4

Effect of capsazepine on the respiratory response to microinjection of capsaicin into the commissural nucleus of the solitary tract: (a) respiratory frequency (f), (b) tidal volume (VT) and (c) minute ventilation (V̇E). Capsazepine (1 nmol) or vehicle (35% ethanol in normal saline) was injected into the cNTS of urethane-anaesthetized, spontaneously breathing rats and allowed to act for 10 min prior to injection of capsaicin (1 nmol, arrow). Values are the mean of four animals and vertical bars show s.e.mean. ^*P<0.05; ^**P<0.01 versus vehicle-capsaicin (ANOVA followed by Fisher's LSD test).

Figure 5

Effect of the NK₁ tachykinin receptor antagonist, RP 67580, on the respiratory response to microinjection of capsaicin into the commissural nucleus of the solitary tract (cNTS): (a) respiratory frequency (f), (b) tidal volume (VT) and (c) minute ventilation (V̇E). RP 67580 was injected into the cNTS of urethane-anaesthetized, spontaneously breathing rats and allowed to act for 10 min prior to microinjection of capsaicin (arrow, 1 nmol) or vehicle (25% ethanol in normal saline). Values are the mean of three to five animals and vertical bars show s.e.mean. ^*P<0.05, response in presence of 1 nmol RP 67580 significantly different from vehicle-capsaicin (ANOVA followed by Fisher's LSD test).

Figure 6

Effect of the NK₂ tachykinin receptor antagonist SR 48968, on the respiratory response to microinjection of capsaicin into the commissural nucleus of the solitary tract (cNTS): (a) respiratory frequency (f), (b) tidal volume (VT) and (c) minute ventilation (V̇E). SR 48968 was injected into the cNTS of urethane-anaesthetized, spontaneously breathing rats and allowed to act for 10 min prior to microinjection of capsaicin (arrow, 1 nmol) or vehicle (25% ethanol in normal saline). Values are the mean of three to five animals and vertical bars show s.e.mean. ^* and ^**, P<0.05 and P<0.01 respectively, response in presence of SR 48968 significantly different from vehicle-capsaicin (ANOVA followed by Fisher's LSD test).

Figure 7

Effect of the NK₃ tachykinin receptor antagonist, SR 142801, on the respiratory response to microinjection of capsaicin into the commissural nucleus of the solitary tract (cNTS): (a) respiratory frequency (f), (b) tidal volume (VT) and (c) minute ventilation (V̇E). SR 142801 was injected into the cNTS of urethane-anaesthetized, spontaneously breathing rats and allowed to act for 10 min prior to microinjection of capsaicin (arrow, 1 nmol) or vehicle (25% ethanol in normal saline). Values are the mean of three to five animals and vertical bars show s.e.mean. ^* and ^**, P<0.05 and P<0.01 respectively, response in presence of SR 142801 antagonist significantly different from vehicle-capsaicin (ANOVA followed by Fisher's LSD test).