Substance P receptors (SPR) modulate nociceptive transmission within the spinal cord. The effects of IV anesthetics on SPR are not clear. In this study, we investigated the effects of IV anesthetics on SPR expressed in Xenopus oocytes. We examined the effects of ketamine, pentobarbital, propofol, and tramadol on SP-induced Ca(2+)-activated Cl(-) currents mediated by SPR expressed in Xenopus oocytes using a whole-cell voltage clamp. Ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, but propofol and tramadol had little effect on the currents. We also studied the effects of ketamine and pentobarbital on [(3)H]-SP to SPR. Ketamine and pentobarbital inhibited the specific binding of [(3)H]-SP to SPR expressed in Xenopus oocytes. Scatchard analysis of [(3)H]-SP binding revealed that ketamine and pentobarbital decreased the apparent dissociation constant for binding and maximal binding, indicating noncompetitive inhibition. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ketamine and pentobarbital on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that ketamine and pentobarbital inhibit SPR function. The mechanism of their inhibition on SPR function could not be through activation of the PKC pathway and may be due to noncompetitive displacing the SP binding.
Implications: We investigated the effects of IV anesthetics on substance P receptors (SPR) expressed in Xenopus oocytes. Ketamine and pentobarbital inhibit SPR function via noncompetitive displacing SP binding. The findings imply that the inhibition of SPR function by these compounds may play a role in the analgesic effects of these IV anesthetics.