'The following abbreviations have been used in the text; I3-L-ODAP, I3-N-uxalyl-L-a,l3diaminu-prupiunic acid; ACPD, Trans-l-aminu-cydupentyl-I,3-dicarbuxylate; AMPA, a­ aminu-3-hydruxy-5-methyl-isoxazole-4-propionate; AP4, 2-amino-4-phosphonobutyrate; AP5, 2-amino-5-phuphonovalerate; ASP, aspartate; CNQX, 6-cyano-7-nitro-quinoxaline-2,3-dione; CPP, 3-(2-earboxypiperazin-4-yl)prupyl-l -phosphate; cyelo-Leu, eydo-Ieucine; DAA, D-a­ amino-adipate; DGG, y-D-glutamylglycine; DNQX, 6,7-dinitro-quinoxaline-2,3dione; EAA, excitatory amino acids; GABA, gamma-aminu-butyric acid; GDEE, glutamate diethyl ester; GLU, glutamate; GL Y, glycine; HA-966, 3-amino-l-hydroxypyrrolidone-2; lBO, ibotenate; IP, inositol phosphate; KA, kainate; KYN, kynurenate; MK-801, dibenzoeyclohepteneimine; NMDA, N-methyl-D-aspartate; PCP, phencyclidine; QA, quisqualate; SER, serine; SOP, serine­ O-phosphate; TCP, 1-[1-(2-thienyl)-eyclohexyIJpiperidine

The Excitatory Amino Acid Receptors: Their Classes, Pharmacology, and Distinct Properties in the Function of the Central Nervous System

Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

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Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.

/pdf/glutamate-as-a-neurotransmitter-in-the-brain-review-of-35ygfs8oah.pdf

Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology

2. Evidence for A m i n o Acids as T ransmi t t e r s . . . . . . . . . . . . . . . . . . . . 99 2.1. Synthesis and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2.2. Synapt ic Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.3. Postsynapt ic Act ion . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 2.4. Postsynapt ic An tagon i s t s . . . . . . . . . . . . . . . . . . . . . . . . . 103 2.5. Inac t iva t ion and R e m o v a l . . . . . . . . . . . . . . . . . . . . . . . . . 104

Amino acid transmitters in the mammalian central nervous system

https://www.cell.com/trends/pharmacological-sciences/pdf/0165-6147(90)90038-A.pdf

Structure-activity relationships in the development of excitatory ammo acid receptor agonists and competitive antagonists

THE anions of aspartic and glutamic acids have potent excitatory action upon spinal neurones (CURTIS, PHILLIS and WATKINS, 1960); this is in marked contrast to the strongly depressant action exhibited by their respective a-decarboxylation products, 0-alanine and y-amino-n-butyric acid (GABA) (CURTIS, PHILLIS and WATKINS, 1959). The latter amino acids cause no significant change in the membrane resting potential of motoneurones, which is strong evidence that these substances are not inhibitory transmitter agents within the mammalian spinal cord. On the other hand, the excitant amino acids cause depolarization of spinal neurones, and consequently one of them or a related substance may have excitatory transmitter function within the nervous system. This possibility has led to a survey of the activity of compounds structurally related to both series of amino acids.

The excitation and depression of spinal neurones by structurally related amino acids.

THE importance of a low but constant concentration of calcium ions in the extracellular fluid bathing nerve cells and fibres is now well established and the experimental evidence points to a connection between the degree of membrane calcification and its permeability to sodium and potassium ions (BRINK, 1954; HODGKIN, 1958; SHANES, 1958; MULLINS, 1959). The location of mammalian spinal neurones makes it difficult to alter the ionic composition of the extracellular fluid around them. However, by the recent techniques of electrophoretic injection into the environment of cells, compounds can now be applied which specifically raise or lower the concentrations of certain extracellular ions. The anions of certain acidic amino acids excite the spinal neurones of the cat (CURTIS, PHILLIS and WATKINS, 1960). Although these acids themselves complex calcium ions only very weakly, it is noteworthy that the structurally related compounds of the Versene group are the most powerful of the known calcium complexing agents. It was of interest therefore to study the effects of these and other sequestering agents upon spinal neurones. The substances were chosen so as to cover a wide range both in their structure and in the stability of the complexes which they form with calcium ions. The reason for this selection was to render easier a differentiation of effects due primarily to the chelation of free extracellular calcium ion from those, if any, due to a direct interaction of the substances with membrane components. This latter mechanism probably accounts for the excitant and depressant actions of amino acids related to glutamic and y-amino-n-butyric acids respectively (cf. CURTIS and WATKINS, 1960). M E T H O D S

The excitation of spinal neurones by the ionophoretic application of agents which chelate calcium.

MANY investigators have shown that a substance with pharmacological effects resembling those of acetylcholine (ACh) may be extracted from mammalian brain (for reviews see FELDBERG, 1945, 1957; HEBB, 1957, 1963). A similar substance is also released from the cerebral cortex (ELLIOTT, SWANK and HENDERSQN, 1950; MACINTOSH and OBORIN, 1953 ; MITCHELL, 1963), and pharmacological evidence indicates that ACh or a related ester may be an important transmitter in the CNS (see FELDBERG, 1945, 1950, 1957). Alternatively the cholinomimetic substance released from the cortex may be associated with metabolic processes (FELDBERG, 1950; WHITTAKER, 1963) not directly involved in synaptic transmission. ACh is synthesized by brain extracts and this synthesized product has been chemically identified (STEDMAN and STEDMAN, 1937). However, such extracts may also synthesize other cholinomimetic substances (NACHMANSOHN, HESTRIN and VORIPAIEFF, 1949 ; MIDDLETON and MIDDLETON, 1949 ; KOREY, DE BRAGANZA and NACHMANSOHN, 1951 ; HENSCHLER, 1956; MORRIS, 1961). HENCSHLER (1956) demonstrated the presence of a small quantity of ACh (about 60 ,umg/g) in beef brain extracts, but, since post mortem losses were considerable, no estimate could be given for the amounts of substances originally present. As yet, no conclusive evidence has been presented to show that the cholinomimetic substance originally present in brain is ACh and not a related ester (see also AMBACHE, 1954; PFEIFFER, 1959). Such a proof is essential before ACh may be accepted as a transmitter in the CNS. The uncertainty regarding the identity of the cholinomimetic substance in brain led PFEIFFER (1959) to speculate that the cholinergic transmitter may be a substance related to acetyl-/I-methylcholine, while more recently HOSEIN and co-workers (HOSEIN and PROULX, 1960, 1962; HOSEIN and ARA, 1962; HOSEIN, PROULX and ARA, 1962; HOSEIN and ORZECK, 1963) have claimed that ACh represents only a small proportion of the cholinomimetic activity of brain extracts, the predominant activity being due to betaine esters and acetylcarnitine. In the present experiments, advantage has been taken of recently developed techniques for separating brain homogenates into histologically identifiable components (GRAY and WHITTAKER, 1962; DE ROBERTIS, PELLEGRINO DE IRALDI, RODRIGUEZ DE LOREZ ARNAIZ and SALGANICOFF, 1962) under conditions in which synthesis would be minimal. In order to investigate the nature of the cholinomimetic activity of a ‘crude mitochondrial fraction’ from brain, the technique of parallel biological assay (CHANG and GADDUM, 1933) has been applied to both a crude extract and the various active fractions obtained by electrophoretic and chromatographic separation of this crude extract. The cholinomimetic activity of the ‘crude mitochondrial fraction’ is attributable to its content of synaptic terminals (GRAY and WHITTAKER, 1962; DE ROBERTIS et al., 1962; RYALL, 1964). Some of this work was communicated to the

J. C. Watkins

Papers

The excitation and depression of spinal neurones by structurally related amino acids.

The excitation of spinal neurones by the ionophoretic application of agents which chelate calcium.

The cholinomimetic activity of extracts of brain nerve terminals.