Substance P hyperpolarizes vagal sensory neurones of the ferret

1. Intracellular recordings were made in intact and in acutely dissociated vagal afferent neurones (nodose ganglion cells) of the ferret to investigate the effects of substance P(SP). 2. In current-clamp recordings, SP (100 nM) applied by superfusion hyperpolarized the membrane potential (7 +/- 0.7 mV; mean +/- S.E.M.; n = 105) and decreased the input resistance in 80% of the neurones. With voltage-clamp recording, SP produced an outward current of 3 +/- 0.2 nA (n = 10). 3. The SP current was concentration dependent with an estimated EC50 of 68 nM. The SP-induced hyperpolarization or current was mimicked by the tachykinin receptor NK1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASM-SP; 100 nM; n = 10) and blocked by the NK1 antagonist CP-96,345 (10 nM; n = 6), but not by the NK2 antagonist SR48968 (100 nM; n = 4). No measurable change in membrane potential or input resistance was observed with application of either [beta-Ala8]neurokinin A or senktide, selective NK2 and NK3 receptor agonists, respectively (100 nM; n = 3 for each agonist). 4. The reversal potential (Erev) for the SP outward current was -85 +/- 2.5 mV (n = 4). The Erev for the SP response shifted in a Nernstian manner with changes in extracellular potassium concentration. Alterations in extracellular sodium or chloride concentrations had no significant effect on the Erev for the SP response (n = 3 for each ion). 5. Nominally Ca(2+)-free external solution abolished the SP response. Removal of magnesium from the extracellular solution had no effect on the response. 6. Caesium (100 microM), barium (1 mM), tetraethylammonium (TEA; 5 mM), apamin (10 nM) and 4-aminopyridine (4-AP; 4 mM) each completely prevented the SP response (n > or = 3 for each). 7. These results indicate that SP, via an NK1 receptor, can induce a Ca(2+)-dependent outward potassium current which hyperpolarizes the resting membrane potential of vagal afferent somata.