Protein kinase-mediated reciprocal modulatory changes in anesthetic sensitivity of (BK)-K +- and GABA-A receptor-gated conductances in guinea-pig sympathetic neurons

(1) The interaction of substance P (SP)-mediated synaptic transmission with general anesthetics remains unknown. (2) Intracellular recordings were obtained from guinea-pig inferior mesenteric ganglion neurons to study monosynaptic responses to exogenous SP and GABA. (3) Propofol (1–100 μM) caused an increase in SP-evoked inward current responses and a concurrent decrease in peak amplitude of the afterspike hyperpolarization of intermittently evoked action potentials. These effects were occluded by the (BK)-K +-channel-selective blocker charybdotoxin (10 nM), and prevented by the protein kinase inhibitor staurosporine (100 nM). (4) Propofol also increased GABA-evoked current ( I GABA) responses. (5) When elicited during a SP response, I GABA was significantly diminished compared to control. In the presence of staurosporine (100 nM), the inhibitory effect of SP upon I GABA was abolished, and the propofol-induced augmentation of I GABA was significantly increased. (6) Thus, SP-evoked protein kinase activity produced reciprocal changes in anesthetic sensitivity of (BK)-K +- and GABA A-receptor-gated currents of these sympathetic neurons.