Effects of Substance P on Medial Vestibular Nucleus Neurons in Guinea-pig Brainstem Slices

The undecapeptide substance P (SP) has been recently implicated in the control of vestibular function. In particular, it seems to be co-localized with glutamate in approximately half of the primary vestibular afferents in mammals. Using intracellular recordings in guinea-pig brainstem slices, we have investigated the effects of SP and of several agonists of the three known tachykinin receptor subtypes (NK₁, NK₂ and NK₃) on the three main types (A, B and B+LTS) of guinea-pig medial vestibular nucleus neurons (MVNn) that we had previously described. SP could induce two distinct kinds of effects on all types of MVNn. Whereas around half of them were depolarized and had their membrane resistance increased by SP, ∼ 10% of all MVNn were in contrast hyperpolarized and inhibited while their membrane resistance was decreased. Both responses persisted under conditions of blockade of synaptic transmission, and were thus due to the activation of postsynaptic binding sites. The SP-induced membrane depolarization could not be reproduced with any one of the specific agonists of the three tachykinin receptor subtypes, nor was it blocked by the specific NK₁ receptor antagonists GR 82334 and CP 99994. This effect might therefore be due to the activation of a new, pharmacologically distinct, 'NK₁-like' receptor. Only the hyperpolarizing effects, which were in contrast mimicked by the specific NK₁ receptor agonists GR 73632 and Sar⁹, Met (O₂)¹¹]-SP, would be mediated by the few typical NK₁ receptors which have been demonstrated in the medial vestibular nucleus.