Glutamate is the major excitatory amino acid (EAA) neurotransmitter in the central nervous system (CNS). 78 EAA neurones and synapses are distributed widely throughout the CNS, 36 231 but they are concentrated particularly in the hippocampus, 91 the outer layers of the cerebral cortex 91 and the substantia gelatinosa of the spinal cord. 194 Within these regions EAA play key roles in physiological processes including learning and memory (and hence awareness under anaesthesia), central pain transduction mechanisms and pathological processes such as excitotoxic neuronal injury which follows CNS trauma or ischaemia. Thus an understanding of the role of EAA in the CNS is relevant to normal higher brain function and to anaesthesia, analgesia and intensive care. A broad spectrum of pharmacological agents which alter EAA-mediated neurotransmission are already available and many more are under development. These include: (i) drugs that specifically target the release of EAA (e.g. the novel antiepileptic drugs felbamate and lamotrigine), (ii) drugs that modify the interactions of EAA with specific receptors (e.g ketamine) and (iii) volatile and i.v. anaesthetic agents which may have a common mechanism of action that, at least in part, involves EAAmediated neurotransmission. To understand the potential applications of these agents it is necessary to consider first how EAA act at the level of the synapse and the individual neurone. To do so involves a brief outline of EAA receptor subtypes and how their activation affects the postsynaptic neurone. It may then be possible to explain how EAA and their receptors are involved in cognition, anaesthesia, analgesia and neurointensive care and therefore to provide a framework to assess the possible clinical applications of drugs which modify EAA-mediated neurotransmission. Excitatory amino acid neurotransmission A diagrammatic representation of an EAA synapse comprising a presynaptic nerve terminal and a postsynaptic neurone expressing multiple EAA receptor
Since its discovery in 1982, neuropeptide Y (NPY) has been shown to have numerous effects mediated by a growing number of NPY receptors in both the CNS and peripheral nervous system. Perhaps best appreciated is the role of NPY in the control of systemic blood pressure, together with its effects on feeding, anxiety and memory. However, recent evidence increasingly supports an important role for NPY in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. In this review we concentrate on this important aspect of NPY pharmacology and consider mechanisms controlling the expression of NPY and its receptors. In addition, we also present the more recent data describing the other possible roles for NPY-NPY agonists and antagonists may be useful in the treatment of conditions as varied as anorexia, epilepsy, anxiety, depression, hypertension and heart failure.
Chronic constriction injury (CCI) of the sciatic nerve results in persistent mechanical hyperalgesia together with Fos protein expression in the lumbar spinal cord. We have examined the relationship between mechanical hyperalgesia and Fos expression within the lumbar spinal cord on days 14, 35 and 55 after either CCI or sham operation. To determine the role of NMDA receptor mechanisms in the maintenance of hyperalgesia and Fos expression, the NMDA antagonist MK-801 (0.3 mg kg-1 s.c.) was administered daily on days 28 to 34 after operation. CCI animals developed unilateral hind limb hyperalgesia that persisted unchanged from days 14 to 55 of the study. MK-801 treatment reduced hyperalgesia by 57% (p=0.02) on day 35 in CCI animals but did influence hyperalgesia at day 55. In the spinal cord, Fos positive cells were present bilaterally throughout laminae 3-10 at all time points examined in both CCI and sham group animals. Fos counts ipsilateral to the side of injury in laminae 3-10 correlated significantly with hyperalgesia scores in the CCI but not sham animals. MK-801 treatment resulted in a suppression of Fos expression in ipsilateral laminae 3-4 (p=0.0017) and laminae 5-10 (p=0.0026) of CCI animals on day 35. Fos expression in sham group animals was not inhibited by MK-801 treatment at day 35. These results indicate that Fos expression is maintained by differing mechanisms following nerve injury or sham operation. The functional consequences of Fos expression following nerve injury and sham operation are discussed.
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