SUBSTANCE-P HYPERPOLARIZES VAGAL SENSORY NEURONS OF THE FERRET

1. Intracellular recordings were made in intact and in acutely dissoci ated vagal afferent neurones (nodose ganglion cells) of the ferret to investigate the effects of substance P (SP). 2. In current-clamp recor dings, SP (100 nM) applied by superfusion hyperpolarized the membrane potential (7 +/- 0.7 mV; mean +/- S.E.M; n = 105) and decreased the in put resistance in 80 % of the neurones. With voltage-clamp recording, XP produced an outward current of 3 +/- 0.2 nA (n = 10). 3. The SP cur rent was concentration dependent with an estimated EC(50) of 68 nM. Th e XP-induced hyperpolarization or current was mimicked by the tachykin in receptor NK1 agonist Ac-[Arg(6), Sar(9), Met(O-2)(11)]SP(6-11) (ASM -SP; 100 nM; n = 10) and blocked by the NK1 antagonist CP-96,345 (10 n ar; n = 6), but not by the NK2 antagonist SR48968 (100 nar; n = 4). No measurable change in membrane potential or input resistance was obser ved with application of either [beta-Ala(8)]neurokinin A or senktide, selective NK2 and NK, receptor agonists, respectively (100 nM; n = 3 f or each agonist). 4. The reversal potential (E(rev)) for the SP outwar d current was -85 +/- 2.5 mV (n = 4). The E(rev) for the SP response s hifted in a Nernstian manner with changes in extracellular potassium c oncentration. Alterations in extracellular sodium or chloride concentr ations had no significant effect on the E(rev) for the SP response (n = 3 for each ion). 5. Nominally Ca2+-free external solution abolished the XP response. Removal of magnesinm from the extracellular solution had no effect on the response. 6. Caesium (100 mu M), barium (1 mM), t etraethylammonium (TEA; 5 mM), apamin (10 nM) and 4-aminopyridine (4-A P; 4 mM) each completely prevented the XP response (n greater than or equal to 3 for each). 7. These results indicate that SP, via an NK1 re ceptor, can induce a Ca2+-dependent outward potassium current which hy perpolarizes the resting membrane potential of vagal afferent somata.