TACHYKININS AS MEDIATORS OF SLOW EPSPS IN GUINEA-PIG GALLBLADDER GANGLIA - INVOLVEMENT OF NEUROKININ-3 RECEPTORS

1. The effects of endogenous tachykinins and related peptides on intact guinea-pig gallbladder neurones were investigated with single-electrode voltage- and current-clamp recording techniques. 2. Pressure ejection of substance P (100 mu M) caused a long lasting membrane depolarization that was associated with a decrease in input resistance. In cells that were voltage-clamped to their resting membrane potential, substance P activated an inward current. 3. The reversal potentials of the substance P-induced depolarization and in ward current were similar to 0 mV. In a low-Na+ solution, the substance P-induced depolarization and inward current were reduced in amplitude. 4. Substance P increased the excitability of neurones, as evidenced by a greater anodal break activity and an increase in the number of action potentials generated during a depolarizing current pulse. 5. Substance P, neurokinin A (NKA) and neurokinin B (NKB) were applied by superfusion to determine the relative potencies of these tachykinins. NKB was the most potent, with an EC(50) of 24 nM. The EC(50) values for NKA and substance P were 47.8 and 281 nM, respectively. 6. The neurokinin-3 (NK-3) receptor agonist senktide depolarized neurones with an EC(50) of 6.3 nM. Neither the NK-1 receptor agonist [Sar(9),Met(O-2)(11)]-substance P nor the NK-2 receptor agonist [beta-Ala(8)]-NKA (4-10) caused a measurable depolarization. 7. The NK-3 antagonist [Trp(7),beta-Ala(8)]-NKA (4-10) inhibited the responsiveness of gallbladder neurones to substance P with a K-B (dissociation constant of receptor antagonist) of 49 nM, and depressed both capsaicin-induced depolarizations and stimulus-evoked slow EPSPs. 8. These data indicate that tachykinins mediate slow EPSPs in guinea-pig gall-bladder ganglia by activating NK-3 receptors on gall-bladder neurones. It is proposed that in response to inflammation or high intraluminal pressure, tachykinins may be released within ganglia by sensory fibres and act directly on intrinsic neurones to facilitate ganglionic transmission.