Postsynaptic actions of substance P on rat periaqueductal grey neurons in vitro.

The postsynaptic actions of substance P on rat midbrain periaqueductal grey (PAG) neurons were examined using whole-cell patch-clamp recordings in brain slices. Substance P produced an inward current in a subpopulation (60%) of PAG neurons. The substance P induced current was concentration dependent (EC50=27 nM) and was reduced by the NK1, NK2 and NK3 antagonists L-732,138 (20 microM), GR 159897 (3 microM) and SB 218795 (3 microM). The selective NK1, NK2 and NK3 agonists [Sar9,Met(O2)11]-Substance P (100 nM), GR 64349 (300-500 nM) and senktide (300 nM) also produced inward currents in subpopulations of neurons. A greater proportion of substance P-sensitive neurons (70%) than substance P-insensitive neurons (31%) responded to the mu/delta opioid agonist met-enkephalin (10 microM). Substance P reduced the outward current produced by met-enkephalin. The reversal potential of the substance P induced current varied from -5 mV to below -140 mV in the absence of met-enkephalin, and was -105 mV in the presence of met-enkephalin. These results indicate that substance P acts via NK1, NK2 and NK3 receptors to excite subpopulations of opioid-sensitive and insensitive PAG neurons by increasing a non-selective cation conductance and by reducing a K+ current. In addition, substance P has anti-opioid actions that are largely mediated by a reduction in the opioid induced K+ current.