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, approximately 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 82664 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.