Cellular and synaptic effect of substance P on neonatal phrenic motoneurons

Experiments were carried out on the in vitro brainstem-spinal cord preparat ion of the newborn rat to analyse the effects of substance P (SP) on phreni c motoneuron (PMN) activity, In current-clamp mode, SP significantly depola rized PMNs, increased their input resistance, decreased the rheobase curren t and shifted the firing frequency-intensity relationships leftwards, but d id not affect spike frequency adaptation or single spike configuration. The neurokinin receptor agonist NK1 had SP-mimetic effects, whereas the NK3 an d NK2 receptor agonists were less effective and ineffective, respectively. In a tetrodotoxin-containing aCSF, only SP or the NK1 receptor agonist were still active. No depolarization was observed when the NK1 receptor agonist was applied in the presence of muscarine. In voltage-clamp mode, SP or the NK1 receptor agonist produced an inward current (/(SP)) which was not sign ificantly reduced by extracellular application of tetraethylammonium, Co2+, 4-aminopyridine or Cs+, In aCSF containing tetrodotoxin, Co2+ and Cs+, I-S P was blocked by muscarine. No PMN displayed any M-type potassium current b ut only a current showing no voltage sensitivity over the range -100 to 0 m V, reversing near the expected E-K(+), hence consistent with a leak current . SP application to the spinal cord only (using a partitioned chamber) sign ificantly increased the phrenic activity. Pretreatment with the NMDA recept or antagonist DL-2-amino-5-phosphonovaleric acid (AP5) decreased the C4 dis charge duration and blocked the effect of SP, thus exhibiting an NMDA poten tiation by SP. In conclusion, SP modulates postsynaptically the response of phrenic motoneurons to the inspiratory drive through the reduction of a le ak conductance and the potentiation of the NMDA component of the synaptic i nput.