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• W176128522 abstract "The study of NMDA and other glutamate receptors is a research topic that has been pursued intensively for more than 30 years and there have been a number of other volumes dealing with some aspects of the subject matter of this book. However, the main research emphasis was formerly on topics other than pain, with neurodegeneration/excitotoxicity and synaptic plasticity being major fields of interest [1-3]. The evidence presented in this volume and other recent publications [4, 5] indicates a pivotal role for glutamate acting at the NMDA receptor in the aetiology of inflammatory pain, neuropathic pain, allodynia and ischaemic pain. Available evidence now suggests that glutamate is the pre-eminent transmitter in sensory neurotransmission and that when acting at the NMDA receptor in particular, it has a permissive interaction with the actions of other sensory neural messengers, especially peptides (see chapter by Cumberbatch et al.) which are also released from terminals of nociceptive afferent fibres within the dorsal horn of the spinal cord following a peripheral noxious stimulus. Given this interaction is it relevant to question whether the action of the peptide co-transmitters such as substance P might be a preferable target for a novel analgesic? Glutamate is ubiquitous in the central nervous system and thus the probability of side-effects from blocking its actions (which would not be restricted to those at sensory synapses) would be high. In contrast, peptides such as substance P have a more restricted anatomical localisation and thus blocking their actions might constitute an analgesic strategy with a lower propensity for unwanted side-effects [6]. The single sensory neuropeptide whose actions have been studied in detail is substance P. The molecular pharmacology of the NK1 receptor at which substance P acts is well understood, and a number of potent antagonists at this receptor have been evaluated clinically as potential analgesics [7]. All of the studies where data is in the public domain have had negative outcomes although it is known from PET studies that saturation of CNS NK1 receptors was achieved with the doses of antagonist used in at least some of the published negative reports [8]. Also, the same antagonists were shown to have reproducible antiemetic effects (another action requiring saturation of CNS NK1 receptors) in similar doses to those found ineffective in clinical pain studies [7, 8]. This is not to say that substance P has no role in the neurotransmission processes underlying the perception of pain, but does suggest that blocking the effects of substance P in isolation (and by inference the effects of any other single sensory neuropeptide?) is not sufficient to produce clinical analgesia [8]. On the contrary, perhaps the most important observation we have at our disposal is that NMDA antagonists, specifically the ion-channel blocker ketamine and the competitive antagonist, CPP, which acts at the glutamate recognition site, do produce analgesic effects in man [5]. At doses only marginally higher than the analgesic dose, however, they also produce pronounced adverse effects [5]. This may be due to the global block of NMDA receptor function as referred to above. NMDA receptors are not limited in distribution to the spinal cord and other sensory regions of the CNS and high densities are found in several other areas of the brain (see chapter by Rigby et al.). Thus, the development of NMDA ion-channel blockers, in particular, no longer seems to be a rational approach and has been abandoned by the majority of pharmaceutical companies." @default.
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• W176128522 title "Future prospects for improved analgesic therapy" @default.
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• W176128522 doi "https://doi.org/10.1007/978-3-0348-8139-5_10" @default.
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