The effects of neurokinin-1 receptor agonists on spinal motoneurones of the neonatal rat.
The effects of substance P (SP) and the selective NK1 receptor agonist [Sar9Met(O2)11] substance P on neonate rat spinal motoneurones were examined using intracellular recordings. Bath-administration of SP (0.1-3 microM) or [Sar9Met(O2)11] substance P (0.01-3 microM) induced a tetrodotoxin (TTX)-insensitive (10 microM) depolarization and a tetraethylammoniumchloride (TEA)-sensitive (3 mM) decrease in membrane conductance. The duration of the slow afterhyperpolarizations (AHPs) following the action potentials were significantly reduced (p = 0.003) by both NK1 receptor agonists. The mean duration of the sAHPs (+/- SEM) in control was 67.8 +/- 6.3 ms whereas in the presence of SP and [Sar9Met(O2)11] substance P their duration was reduced to 41.7 +/- 4.6 ms. Low Ca2+ (0.2 mM)-containing artificial cerebrospinal fluid (ACSF) or addition of BaCl2 or CdCl2 (2 mM) reduced the durations of the slow AHPs by 55%. In the presence of these agents SP and [Sar9Met(O2)11] substance P practically abolished the remaining slow AHPs, suggesting that the agonists also reduce a calcium-independent current. None of the effects induced by the NK1 receptor agonists were antagonized by the NK1 receptor antagonists (+/-)-CP-96,345 (10 microM), RP 67580 (1 microM) or GR 82334 (3-5 microM). In conclusion this study demonstrates that SP and [Sar9Met(O2)11] substance P elicit their effects on NK1 receptors by modulating at least two potassium currents, namely IK and ICa(K).
Lepre
M
M
Research and Development Department, Pharmaceuticals Division, CIBA Ltd, Basel, Switzerland.
Olpe
H R
HR
Brugger
F
F
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001713:Biphenyl Compounds / Q000494:pharmacology; D004553:Electric Conductivity; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D009046:Motor Neurons / Q000187:drug effects*; D064729:Neurokinin-1 Receptor Antagonists; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000819:agonists*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects*
D001713:Biphenyl Compounds; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; C079014:GR 82334; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D010803:Physalaemin; C066892:CP 96345