The role of neurokinin and N-methyl- d-aspartate receptors in synaptic transmission from capsaicin-sensitive primary afferents in the rat spinal cord in vitro

Abstract

The rat spinal cord with connected dorsal root ganglia was used to study neurokinin and N-methyl- d-aspartate receptors involved in the sensory synaptic transmission of dorsal horn cells. Selective C-fibre excitation was produced by capsaicin (200–500 nM) administered to the dorsal root ganglions. Sixty-nine per cent of dorsal horn cells responded with a postsynaptic depolarization and enhanced synaptic activity, recorded via intracellular electrodes, to capsaicin-activated primary afferent input. Dorsal horn neurons activated by the capsaicin-evoked input were also excited by a 1-min perfusion of the neurokinin-1 receptor agonists substance P methyl ester or GR73 632 and by the neurokinin-2 agonist neurokinin-A. These cells were also depolarized by N-methyl- d-aspartate. Responses to substance P methyl ester and GR73 632 were selectively reduced by the neurokinin-1 receptor antagonist CP96 345, and responses to neurokinin-A were completely blocked by the neurokinin-2 receptor antagonist MEN 10 376. The depolarization evoked by N-methyl- d-aspartate was not altered by either of the antagonists, but was completely blocked by the selective N-methyl- d-aspartate receptor antagonist (−)-2-amino-5-phosphonovaleric acid. Capsaicin-evoked responses in the dorsal horn were inhibited by MEN 10 376 (63 ± 13% inhibition) but no significant change was observed with CP96 345. The N-methyl- d-aspartate receptor antagonist (−)-2-amino-5-phosphonovaleric acid consistently inhibited the capsaicin-induced response by 76 ± 14%. Combination of (−)-2-amino-5-phosphonovaleric acid and MEN 10 376 produced an almost complete abolition of the capsaicin-evoked depolarization. However, when (−)-2-amino-5-phosphonovaleric acid and CP96 345 were perfused together there was no alteration from the response to (−)-2-amino-5-phosphonovaleric acid alone. These data suggest that activation of dorsal horn neurons by polymodal nociceptors, the most abundant type of capsaicin sensitive C-fibres, involve mainly neurokinin-2 rather than neurokinin-1 receptors. A strong N-methyl- d-aspartate receptor-mediated component is also involved. The N-methyl- d-aspartate and neurokinin-2 receptors may be co-activated by nociceptive input and act together to produce slow synaptic potentials and prolonged excitability changes.