M.N. Perkins

An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid

Abstract Kynurenine and related compounds are endogenous metabolites of tryptophan which have previously been found to be convulsant in animals. We now report that kynurenine, kynurenic acid, nicotinic acid do not excite neurones in the cerebral cortex, but that quinolinic acid is an effective excitant. Kynurenine had no effect on responses to quinolinic acid, glutamate or N-metyl- D -aspartate (NMDA) and did not block depressant responses to GABA, glycine or 5-hydroxytryptamine. Suprisingly kynurenic acid proved a powerful antagonist of quinolinic acid, NMDA and quisqualic acid, but showed no preferential antagonism to one agonist. It did, however, show a preference for reducing quinolinic acid responses compared to acetylcholine responses.

Quinolinic acid: regional variations in neuronal sensitivity

The excitatory action of quinolinic acid has been examined on neurons in different parts of the rat CNS. When applied by microiontophoresis quinolinic acid excited cells in the cerebral cortex, hippocampus and neostriatum, but even when applied from electrodes which produced responses in these areas, quinolinic acid was ineffective in the cerebellum and spinal cord. Like most excitants tested in other studies, L-glutamate was excitatory to all cells examined. As an endogenous compound, therefore, quinolinic acid may merit special attention as a potential neurotransmitter in brain.

Phosphonate analogues of carboxylic acids as aminoacid antagonists on rat cortical neurones

Phosphonate analogues of carboxylic acids have been tested as antagonists of excitatory aminoacids in rat cerebral cortex. (+/-)--2-Amino-7-phosphono-heptanoic acid and the (-)-D-isomer of the pentanoate derivative were more potent and selective antagonists of N-methyl-D-aspartate (NMDA) than compounds tested previously. The results support the view that a distinct population of receptors exists which are preferentially activated by NMDA.

Actions of kynurenic acid and quinolinic acid in the rat hippocampus in vivo.

An iontophoretic study was made of the interaction of kynurenic acid with excitatory amino acids in the hippocampus and with the commissural input from the contralateral hippocampus in the rat. The results showed that kynurenic acid was an effective blocker of synaptic transmission in the hippocampus in vivo, adding further support to the idea that an excitatory amino acid is involved in neurotransmission in this structure. In addition there was an increase in the specificity of kynurenate as an antagonist of excitatory amino acids in the hippocampus compared with neocortex, with much more activity being shown toward the NMDA-preferring rather than the quisqualic acid-preferring receptor. Kynurenic acid was also able to distinguish partially between quinolinic acid and NMDA, supporting the possibility that two types of NMDA/quinolinate receptors exist in the hippocampus.

BLOCKADE OF STRIATAL NEURONE RESPONSES TO MORPHINE BY AMINOPHYLLINE: EVIDENCE FOR ADENOSINE MEDIATION OF OPIATE ACTION

1 The responses of cortical and striatal neurones to morphine and adenosine applied iontophbretically have been studied in the male rat. 2 The majority of cells (57%) within the corpus striatum were profoundly inhibited, and a smaller proportion (18%) excited by morphine. Adenosine depressed the firing rate of 30/44 cells in the striatum, excitation never being observed. In contrast, the responses of cortical cells to morphine were typically weak and required longer ejection pulses to effect comparable changes in firing rate. 3 Aminophylline applied iontophoretically, as an anion, proved able to antagonize reversibly both morphine and adenosine in parallel. 4 On a number of cells, γ‐aminobutyric acid (GABA) was used as a control depressant but aminophylline did not appear to reduce these responses. 5 The responses to morphine (both inhibitory and excitatory) were not easily antagonized by naloxone. Typically, excitatory responses were easier to antagonize than the inhibitory ones. 6 It is concluded that a consequence of the interaction of morphine with its receptors may be the release of adenosine which subsequently produces the inhibition observed with morphine.

Actions of excitatory amino acids and kynurenic acid in the primate hippocampus: A preliminary study

Orthodromic evoked potentials of CA1 pyramidal cells were studied in superfused slices of marmoset hippocampus. N-methylaspartate, quinolinic acid and quisqualic acid depressed the responses, but only the former two compounds appeared to be antagonized by 2-amino-5-phosphonovalerate. Kynurenic acid also reduced the orthodromic evoked responses but had no effect on antidromic potentials, the blocking action therefore probably resulting from an interference with synaptic transmission. The study reveals receptors for N-methylaspartate, quisqualate, quinolinate and kynurenic acid in the primate hippocampus broadly comparable with those previously studied in non-primate vertebrates.

Activity of the enantiomers of 2-amino-5-phosphono-valeric acid as stereospecific antagonists of excitatory aminoacids

The (+) and (−) enantiomers of 2-amino-5-phosphono-valeric acid have been separated and tested as antagonists of aminoacid excitation of neurones in rat cerebral cortex. The compounds were applied by microiontophoresis. The (−)-isomer was about 8–10 times more active than the racemate in blocking responses to N-methyl-d-aspartate, and was better able to distinguish between N-methyl-d-aspartate and glutamate. The results support the concept of a distinct population of receptors for N-methyl-d-aspartate.

Kinins and Pain

Publisher Summary This chapter provides an overview of the kinins and pain. Pain signals are generated in fine afferent C- and Aδ nerve fibers, which respond to a range of intense physiological stimuli including heat, cold, and potentially noxious chemicals. Indeed all tissues, with the exception of the neuropil of the central nervous system (CNS), are innervated by such afferent fibers, although their properties differ markedly depending on whether they are somatic afferents. In the viscera, there is less evidence for afferents that serve specific nociceptive functions under normal physiological conditions. However, when significant tissue damage occurs, pain is often more persistent and is associated with inflammation and hyperalgesia around the inflamed region. Kinins are likely to be among the first agents produced at sites of injury or inflammation and they serve critical roles in signaling tissue distress as well as organizing responses to injury and subsequent repair. Important in this orchestrated series of events is the activation of fine afferents to signal immediate pain followed by prolonged sensitization to exogenous stimuli to minimize further tissue disturbance. Kinins interact specifically with B2 receptors expressed on sensory neurons and transduce signals that alter membrane excitability and cellular chemistry.

Hyperalgesia in rats following intracerebroventricular administration of endotoxin : effect of bradykinin B1 and B2 receptor antagonist treatment

&NA; The present study investigated the development of thermal and mechanical hyperalgesia following intracerebroventricular (i.c.v.) injections of E. coli lipopolysaccharide (LPS). Hind paw withdrawal to von Frey filament stimulation and thermal withdrawal latencies were measured before and up to 24 or 48 h following an i.c.v. injection of LPS (dose range: 0.02–200 &mgr;g). Thermal and mechanical hyperalgesia were evident by 6 h after LPS injection. LPS‐induced hyperalgesia was reversed by the B2 receptor antagonist, HOE 140 (10–30 pmol), when administered i.c.v. but not systemically (0.01‐1 mmol/kg, i.v.). Central co‐administration of the B1 receptor antagonists, des‐Arg9‐Leu8 Bk (0.1‐1 nmol) or des‐Arg10 HOE 140 (0.1‐1 nmol) had no effect on thermal or mechanical hyperalgesia. LPS‐induced hyperalgesia was also inhibited by indomethacin administered either i.c.v. (10 nmol) or i.v. (1 &mgr;mol/kg). These results indicate that administration of endotoxin to the CNS induces the development of hyperalgesia and that this response involves the activity of kinins, via the stimulation of centrally located B2 receptors, and the formation of prostanoids.

In vivo release of [3H]‐purines by quinolinic acid and related compounds

1 In vivo release of [3H]‐purines from the cortex of anaesthetized rats was measured and the actions of excitatory amino acids and analogues investigated. 2 High KCl, N‐methyl‐dl‐aspartate (NMDLA) and quinolinic acid produced a large increase in basal release of labelled materials. Glutamate, quisqualate and kainate had less effect. 3 The N‐methyl‐d‐aspartic acid (NMDA)‐preferring receptor antagonist, 2‐amino‐7‐phosphono‐heptanoic acid, significantly reduced the release evoked by NMDLA and quinolinate but not that produced by the other agonists. 4 Kynurenic acid, a compound metabolically related to quinolinic acid, reduced the release due to NMDLA and quinolinate but not glutamate. 5 The results add further support to the suggestion that quinolinic acid acts on the NMDA‐preferring receptor.