Respiratory actions of tachykinins in the nucleus of the solitary tract: Characterization of receptors using selective agonists and antagonists

Abstract

1. The respiratory response to microinjection of tachykinins and analogues into the commissural nucleus of the solitary tract (cNTS) of urethane-anaesthetized rats was investigated in the presence and absence of selective tachykinin NK1, NK2 and NK3 antagonists (RP 67580, SR 48968 and SR 142801, respectively). 2. All tachykinins, except for the selective NK2 agonist, [Nle10]-NKA(4-10), increased tidal volume (VT). The rank potency order of naturally-occurring tachykinins was neurokinin A (NKA) ≥ substance P (SP) > > NKB, whereas the rank order for selective analogues was senktide ≥ septide > > [Sar9,Met(O2)11]-SP > > [Nle10]-NKA(4-10). Septide (NK1-selective) and senktide (NK3-selective) were 22 fold more potent (pD2 ~ 12) at stimulating VT than SP (pD2 ~ 10.5). 3. Tachykinin agonists produced varying degrees of respiratory slowing, independent of changes in VT. At doses producing maximum stimulation of VT, agonists induced either a mild (< 10 breaths min-1 decrease; SP and septide), moderate (10-25 breaths min-1 decrease; NKA, NKB and [Sar9,Met(O2]-SP) or severe (~40 breaths min-1 decrease; senktide) bradypnoea. [Nle10]-NKA(4-10) produced a dose-dependent bradypnoea without affecting VT. 4. RP 67580 significantly attenuated the VT response to SP (33 pmol) and NKA (10 pmol) but not NKB (100 pmol). In the presence of RP 67580, the mild bradypnoeic response to NKB was significantly enhanced whereas SP and NKA induced a bradypnoea which was not observed in the absence of RP 67580. SR 48968 had no effect on the VT response to SP or NKB, markedly enhanced the VT response to NKA and completely blocked the bradypnoeic response to [Nle10]-NKA(4-10). Only SR142801 attenuated the VT response to NKB. 5. The present data suggest that all three tachykinin receptors (NK1, NK2 and NK3) are present in the cNTS and are involved in the central control of respiration.