Carpenter, Katherine Jane; (2001) Pharmacological modulation of processes contributing to spinal hyperexcitability: Electrophysiological studies in the rat. Doctoral thesis (Ph.D.), University College London.

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Abstract

Two of the most effective analgesic strategies in man are (i) blockade of the NMDA receptor for glutamate, which plays a major role in nociceptive transmission and (ii) augmentation of inhibitory systems, exemplified by the use of ketamine and the opioids respectively. Both are, however, are associated with side effects. Potential novel analgesic targets are investigated here using in vivo electrophysiology in the anaesthetised rat with pharmacological manipulation of spinal neuronal transmission. Three different approaches were used to target NMDA receptors: (i) glycine site antagonists (Mrz 2/571 and Mrz 2/579), (ii) antagonists selective for receptors containing the NR2B subunit (ifenprodil and ACEA-1244), (iii) elevating the levels of N-acetyl-aspartyl- glutamate (NAAG), an endogenous peptide, by inhibition of its degradative enzyme. All agents produced selective inhibitions of noxious-evoked activity of dorsal horn neurones, with differing profiles. Effects of NAAG elevation were enhanced after inflammation and neuropathy, probably a result of agonist activity at the mGlu3 metabotropic glutamate receptor rather than reported NMDA receptor partial agonist properties. The mu opioid receptor agonist methadone has affinity for the NMDA receptor. Spinal application of racemic methadone and the weak opioid optical isomer d-methadone, revealed that the inhibitory effects were predominantly opioid receptor mediated. Functional NMDA receptor blockade was not apparent. Nociceptin/orphanin FQ (NC/OFQ) differs from the classical opioids and can, like NMDA receptor antagonists, attenuate spinal hyperexcitability. Pre-synaptic effects were enhanced after peripheral inflammation. Peripheral administration caused excitations of primary afferent fibres. Three putative antagonists were studied. [Phe1 ? (C H2- NH)Gly2]nociceptin-(1-13)-NH2 was as potent as nociceptin in inhibition of neuronal responses and is now recognised as a partial agonist. [N-Phe1]nociceptin(1-13)NH2 was similarly unreliable, but J-113397, proved more fruitful. Protons are implicated in inflammatory pain and peripheral hyperalgesia. I demonstrated activation of primary afferent fibres by peripheral administration of low pH solutions, the first electrophysiological study to do so in vivo. The overall results provide a number of pharmacological strategies that may lead to a better control of pain. The thesis also sheds some light on a fundamental question in neurobiology, in describing both peripheral and central mechanisms that underlie normal transmission and aspects of plasticity in pain pathways.

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