AN NK1 RECEPTOR-DEPENDENT COMPONENT OF THE SLOW EXCITATION RECORDED INTRACELLULARLY FROM RAT MOTONEURONS FOLLOWING DORSAL-ROOT STIMULATION

Intracellular recording from lumbar motoneurons of the neonatal rat sp inal cord in vitro was used to study how recently developed non-peptid e antagonists such as SR-140333 and SR-48698, known to block distinct subtypes of tachykinin receptors peripherally, might affect synaptic t ransmission elicited by electrical stimulation of dorsal root fibres. SR-140333 (1 mu M) preferentially antagonized responses mediated by an exogenously applied agonist acting on the NK1 receptor subclass, whil e SR-48968 (0.5 mu M) preferentially reduced responses mediated by an exogenously applied agonist acting on the NK2 receptor subclass. SR-48 968 did not affect fast or slow excitatory postsynaptic potentials (EP SPs) or 'wind-up' responses induced by repetitive, low-frequency stimu lation (mimicking certain types of nociceptive input); binding studies using this radiolabelled ligand disclosed specific binding activity ( 21 fmol/mg protein) selectively displaced by an NK2 receptor agonist. SR-140333 reduced the late component of fast and slow EPSPs, and of wi nd-up. Pharmacological block of ionotropic glutamate receptors abolish ed all dorsal root-evoked EPSPs. In comparison to glutamate receptor b lockers, SR-140333 was a weaker antagonist of slow synaptic responses, though it displayed preferential antagonism towards some components o f the wind-up phenomenon. The present results provide evidence obtaine d with a novel NK1 antagonist that a neuropeptide (presumably substanc e P), although not directly released by primary afferents onto motoneu rons, is a neurotransmitter (acting via NK1 receptors) in the pathway mediating slow synaptic responses of motoneurons, and is presumably in volved in signalling nociceptive inputs from the periphery.