EFFECTS OF SUBSTANCE-P ON MEDIAL VESTIBULAR NUCLEUS NEURONS IN GUINEA-PIG BRAIN-STEM SLICES

The undecapeptide substance P (SP) has been recently implicated in the control of vestibular function. In particular, it seems to be co-loca lized with glutamate in approximately half of the primary vestibular a fferents in mammals. Using intracellular recordings in guinea-pig brai nstem slices, we have investigated the effects of SP and of several ag onists of the three known tachykinin receptor subtypes (NK1, NK2 and N K3) on the three main types (A, B and B-LTS) of guinea-pig medial vest ibular nucleus neurons (MVNn) that we had previously described. SP cou ld 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, similar to 10% of all MVNn were in contrast hyperpol arized and inhibited while their membrane resistance was decreased. Bo th responses persisted under conditions of blockade of synaptic transm ission, and were thus due to the activation of postsynaptic binding si tes. The SP-induced membrane depolarization could not be reproduced wi th any one of the specific agonists of the three tachykinin receptor s ubtypes, nor was it blocked by the specific NK1 receptor antagonists G R 82334 and CP 99994. This effect might therefore be due to the activa tion of a new, pharmacologically distinct, 'NK1-like' receptor. Only t he hyperpolarizing effects, which were in contrast mimicked by the spe cific NK1 receptor agonists GR 73632 and [Sar(9), Met (O-2)(11)]-SP, w ould be mediated by the few typical NK1 receptors which have been demo nstrated in the medial vestibular nucleus.