Urch, Catherine Elizabeth; (2002) The postnatal development of nociceptive transmission: the role of the NMDA receptor complex. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this thesis is to examine the role of the N-methyl-D-aspartate (NMDA) receptor complex in the development of spinal nociception within the spinal cord of the rat. In particular the dorsal horn is crucial in the transmission and modulation of nociceptive inputs and undergoes extensive postnatal maturation. In vivo electrophysiological responses to NMDA antagonists or nitric oxide synthase (NOS) inhibitors together with in vitro immunohistochemical assessment of postnatal receptor distribution were used to assess alterations in the NMDA receptor. Immunocytochemical staining of the whole spinal cord revealed widespread NR1 subunit expression from birth, whilst NR2 subunits underwent most postnatal alteration. NR2B was the predominant subunit at birth and underwent restriction to the adult distribution in lamina II, whilst the NR2A subunit expression was low at birth and became the predominant subunit in the adult. The DRG revealed widespread expression of all the NMDA subunits from P14. In the dissociated cell culture the NR1 positive neurones in the dorsal horn increased from 25-100% with an increase in staining intensity in contrast with the DRG where all the neurones remained NR1 positive albeit with a reduction in staining intensity. These alterations in expression of the NMDA receptor subunits could account for the difference in efficacy of spinally applied 2-amino-5 phophonopentoic acid (AP5) an NMDA receptor antagonist on the responses of convergent dorsal horn neurones. AP5 was significantly more potent in pups compared with adults whilst ketamine, which binds equally to all the NR2 subunits displayed no age related alteration in efficacy. The application of 7NI (a specific nNOS inhibitor) and L-NAME (non-specific NOS inhibitor) revealed no age differences in post-synaptic evoked responses, but displayed a significantly greater inhibition of the primary evoked response at postnatal day (P) 14 compared with P21, 28 or adult. The NMDA receptor has been shown to alter its subunit composition and receptor expression on primary afferents and post-synaptic dorsal horn neurones during development. This alteration may explain the developmental differences seen in convergent dorsal horn neurones to NMDA receptor anatagonist. However in contrast the role nNOS / NO pathway in nociception does not seem to be altered during development.

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