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.
Drew
Geoffrey M
GM
Pain Management Research Institute, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, E25, Sydney, NSW 2006, Australia. gdrew@med.usyd.edu.au
Mitchell
Vanessa A
VA
Vaughan
Christopher W
CW
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004594:Electrophysiology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000166:cytology / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000187:drug effects; D017481:Receptors, Somatostatin / Q000187:drug effects; D018039:Receptors, Tachykinin / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*
D018755:GABA Agonists; D064729:Neurokinin-1 Receptor Antagonists; D024661:Potassium Channels, Inwardly Rectifying; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; D018039:Receptors, Tachykinin; D013373:Substance P; D004744:Enkephalin, Methionine; D001418:Baclofen