Electrophysiological characterisation of tachykinin receptors in the rat nucleus of the solitary tract and dorsal motor nucleus of the vagus in vitro

Abstract

1. Recent studies have shown antagonists at the NK₁ subtype of receptor for tachykinins are anti-emetics and suggested that this may result from blockade of tachykinin-mediated synaptic transmission at a central site in the emetic reflex.

2. We have used intracellular recording in vitro to study the pharmacology of tachykinins in the nucleus of the solitary tract (NST) and dorsal motor nucleus of the vagus (DMNV).

3. Neurones in the NST were depolarized by substance P (SP), the presumed endogenous ligand for the NK₁ receptor and these effects were mimicked by the NK₁ agonists, SP-O-methylester (SPOMe), GR73632 and septide; however, SP was nearly an order of magnitude less potent than the latter two agonists.

4. In the DMNV, SP and NK₁ receptor agonists evoked similar depolarising responses but SP appeared to be more potent than in the NST and was closer in potency to the other agonists.

5. NK₁-receptor antagonists blocked responses to septide and GR73632 in the NST but had little effect on responses to SP and SPOMe. In contrast, in the DMNV the NK₁-receptor antagonists blocked responses to septide and GR73632 but also reduced responses to SP and SPOMe.

6. Neurokinin A (NKA) was almost equipotent with septide and GR73632 in depolarizing both NST and DMNV neurones but these effects were not mimicked by a specific NK₂-receptor agonist. Responses to NKA were unaffected by an NK₂-receptor antagonist; however, the depolarizing effects of NKA were blocked by NK₁-receptor antagonists.

7. Neurones in both DMNV and NST were unaffected by the endogenous NK₃-receptor ligand, neurokinin B and by a specific agonist for this site, senktide.

8. The results with NK₁ receptor agonists and antagonists suggest that the septide-sensitive NK₁ site is involved in the excitation of both NST and DMNV neurones. The ‘classical' NK₁ receptor may play more of a role in the DMNV and a third unknown site may be responsible for the depolarizing response to SP in the NST. The effects of NKA are best interpreted as an action at the septide-sensitive NK₁ site. This raises the possibility that anti-emetic action of the NK₁ antagonists may be due to blockade of NKA transmission at the septide-sensitive site.

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