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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analgesia has been reported to be facilitated by supraspinal nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). In the rostromedial medulla, an important pain-suppressing region, iontophoretically delivered 8-bromo-cGMP excited most single recorded cells (9/10), and methylene blue (a guanylyl cyclase inhibitor) inhibited all cells (7/7). Nitrite and ferrous ions together, shown voltammetrically ex vivo to yield nitric oxide (NO), excited some cells (14/28) and inhibited others (7/28). Methylene blue blocked excitation (3/3) but not inhibition (4/4) by the putative NO. Spontaneous or glutamate-evoked firing was gradually inhibited (23/32) or unaffected by N omega-nitro-L-arginine (a NO synthase inhibitor), but was mostly inhibited by L-arginine (the NO precursor) (23/26), although a rapid onset militated against elevated NO production. These substances, excepting L-arginine, produced changes consistent with an excitatory cGMP-NO cascade contributing to analgesia.
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PMID:Excitation of cells in the rostral medial medulla of the rat by the nitric oxide-cyclic guanosine monophosphate messenger system. 858 98

Most of the previous experimental studies on the antinociceptive effects of electrical spinal cord stimulation (SCS) have focused on short-lasting effects mainly depending on spinal mechanisms. However, patients treated with SCS for chronic pain often report pain relief exceeding the period of stimulation for several hours. The long lasting effect of SCS might not only involve spinal, but also supraspinal mechanisms. A supraspinal region of major importance for the coordination of descending pain inhibition is the periaqueductal grey matter (PAG). The aim of the present microdialysis study, performed in awake freely moving rats, was to investigate if repeated SCS (two 30 min periods separated by a 90 min resting period) alters the extracellular neurotransmitter concentrations in the ventrolateral PAG. In a first series of experiments significantly decreased (-30%; P < 0.05; n = 7) gamma-aminobutyric acid (GABA) levels were detected immediately after the second SCS session. Neither the concentration of serotonin nor that of substance P-like immunoreactivity (SP-LI) was affected by SCS. The decrease of GABA after two SCS sessions was confirmed in a second series of experiments (-30%; P < 0.05; n = 7). No spontaneous decline of GABA was observed in sham-stimulated animals (n = 6). The glutamate concentration was also determined in this latter series of experiments and a significant decrease (-23%; P < 0.05; n = 5) was observed after the second SCS session. As GABA-neurons in the PAG exert a tonic depressive effect on the activity in descending pain inhibitory pathways, a decreased extracellular GABA level in this region, as detected following repeated SCS, might indicate an increased pain inhibition.
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PMID:Repeated spinal cord stimulation decreases the extracellular level of gamma-aminobutyric acid in the periaqueductal gray matter of freely moving rats. 861 26

Nociceptive transmission shows unusual features of sensorial physiology, due to the complex modulation which occurs from the start of the impulse until its final perception. In recent years the dynamic role played in nociception by peripheral structures, such as the 7 and spinal nociceptors and the second order neurones, has been recognized. It is fairly clear how a number of modulators activate and make nociceptors sensitive, accounting for the appearance of clinical features such as primary hyperalgesia, and their persistance. Thus eico sanoides, histamine, bradykinin and others allow considerable control of nociceptor activity. Also, the dorsal horn neurones play an important part in other clinical signs associated with pain, such as mechanical (secondary) hyperalgesia. At this level, some neurotransmitters such as glutamate or the neurokinins seem to be important in central sensibilization phenomena which occur when a painful stimulus is maintained. In fact, continued release of these neurotransmitters implies the expression of certain genes and the production of certain proteins. Knowledge of the relationship between the different neurochemical systems and subsequent changes in their expression in different pathological situations may help to explain the pathophysiology of some clinical signs of neuropathic pain which are at present inexplicable.
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PMID:[Current aspects of nociceptive transmission: peripheral mechanisms and spinal modulation]. 868 Nov 87

The freely diffusible gaseous compound nitric oxide (NO) has recently been discovered to be an important cellular messenger in many organ systems throughout the body. The importance of NO as an intermediary in cell communication in the brain is highlighted by the fact that the excitatory amino acid glutamate, the most abundant central neurotransmitter, is an initiator of the reaction that forms NO. In this article, background information about the discovery of NO, its biochemistry, and a brief summary of some of its peripheral and central actions are given to provide a complete picture of this remarkable novel second messenger. We also discuss how an improved understanding of NO pathway may lead to the identification of novel medications for the treatment of a number of neuropsychiatric conditions, including memory deficits, pain, drug addiction, seizures, bipolar disorder, psychosis, eating disorders, and the treatment of the sequelae of various brain injuries.
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PMID:The nitric oxide pathway: potential implications for treatment of neuropsychiatric disorders. 868 10

Previous studies have suggested that glutamate is a neurotransmitter in ascending somatosensory pathways to the thalamus. The present study examined with quantitative immunohistochemical methods the presence of glutamate in spinothalamic tract terminals of owl monkeys (Aotus trivirgatus). Such terminals in the posterior region, in which a nucleus was recently identified as a specific pain and temperature relay in macaques and humans, were labeled by anterograde transport of wheat germ agglutinin conjugated to horseradish peroxidase, injected into the spinal dorsal horn. Glutamate-like immunoreactivity was demonstrated with a postembedding immunogold procedure using a well-characterized glutamate antiserum. Quantitative analysis of the immunogold labeling demonstrated that the spinothalamic tract terminals contained more than twice the tissue average of glutamate-like immunoreactivity. Enrichment of glutamate-like immunoreactivity was also found in terminals of presumed cortical origin. Presynaptic dendrites, cell bodies and non-vesicle-containing dendrites displayed low levels of glutamate-like immunoreactivity. A strong positive correlation (r = 0.69; P < 0.0001) was found between the density of synaptic vesicles and the density of gold particles in spinothalamic tract terminals, in contrast to a weak negative relationship (r = -0.28; P = 0.089) present in GABAergic presynaptic dendrites. These data provide strong evidence that the gold labeling in the spinothalamic tract terminals represents transmitter labeling, implying that glutamate is a neurotransmitter for ascending nociceptive and thermoreceptive information in primates.
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PMID:Evidence for glutamate as a neurotransmitter in spinothalamic tract terminals in the posterior region of owl monkeys. 872 Nov 53

The development of chronically painful states following peripheral nerve injury may involve different mechanisms depending on the nature and extent of the nerve lesion. The altered spinal neurochemistry of two substances, the excitatory amino acid glutamate operating via the N-methyl-D-aspartate receptor and the endogenous opioid peptide dynorphin, have been implicated in behavioral sequelae that follow partial peripheral nerve injury. In addition, dynorphin has nonopioid functions which may involve the N-methyl-D-aspartate receptor. We investigated two hypotheses: that the development of mechanical allodynia following complete nerve injury is not greatly influenced by the N-methyl-D-aspartate receptor, and that spinal dynorphin and glutamate expression is interdependent. These studies employed sciatic cryoneurolysis, a complete but transient peripheral nerve injury that results in a delayed mechanical allodynia beginning 21-28 days after injury. Rats were administered dizocipline maleate (MK-801) at 0.25 mg/kg twice per day intraperitoneally from days 0-7 or from days 0-21 post-lesion to pre-emptively block the N-methyl-D-aspartate receptor. In a separate group of rats, an antibody to dynorphin was administered intraperitoneally at 16.6 mg/kg twice per day from days 14 to 21 post-lesion. For all groups, the outcome of allodynia behavior was assessed using von Frey filaments at 42 days post-lesion and the resulting dynorphin and glutamate immunoreactivity in the substantia gelatinosa was measured using proportional area stained and relative optical density, respectively. Only the 0-7 day MK-801 treatment increased the resulting mechanical thresholds significantly (mean +/- S.E.M. 7.0 +/- 1.2 g) when compared to saline-injected animals (3.9 +/- 0.6 g). However, this effect did not prevent allodynia since baseline thresholds were 12 or 15 g for each group. With regard to resulting spinal immunoreactivity, anti-dynorphin antibody treatment significantly increased glutamate immunoreactivity when compared to saline-treated animals (mean relative optical density +/- S.E.M. = 807.2 +/- 3.6 versus 779.6 +/- 8.3, respectively; P = 0.01) at 42 days post-lesion. We conclude that the development of allodynia following sciatic cryoneurolysis peripheral nerve injury involved a minimal contribution from N-methyl-D-aspartate receptor activity. In addition, this study demonstrated that decreasing available dynorphin using antiserum had a significant and lasting effect on spinal glutamate expression without altering the outcome of allodynia. These conclusions suggest that etiological mechanisms leading to pain behaviors are not equal for all nerve injuries, and that altering kappa opioid levels can affect glutaminergic pathways at a substantially later time.
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PMID:Pre-emptive dynorphin and N-methyl-D-aspartate glutamate receptor antagonism alters spinal immunocytochemistry but not allodynia following complete peripheral nerve injury. 873 21

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate (Glu) receptor have become the focus of considerable attention as potential neurotherapeutic agents in view of mounting evidence implicating NMDA receptors in acute central nervous system (CNS) injury syndromes such as stroke, trauma, and status epilepticus. In addition, NMDA receptor antagonists are of potential interest for the clinical management of neuropathic pain and preventing the development of tolerance to opiate analgesics. A potentially serious obstacle to the development of NMDA antagonists as neurotherapeutic drugs is the paradoxical fact that whereas these agents do have significant neurotherapeutic potential, they also have psychotogenic and neurotoxic properties. We have been intensively investigating the mechanisms underlying these adverse properties and have discovered several methods of suppressing or preventing their expression. In addition, we have been exploring the possibility that a common mechanism may underlie the psychotogenic and neurotoxic actions of these agents and that this mechanism may have relevance to the pathogenesis of idiopathic psychotic processes such as schizophrenia. In this chapter, we will review our findings pertaining to NMDA antagonists in the dual context of their value as tools for exploring mechanisms underlying neuropsychiatric disturbances, particularly schizophrenia, and their potential promise as therapeutic agents. For additional references and a more complete elaboration of our hypothesis pertaining to NMDA receptor dysfunction and schizophrenia, please see a recent review (Olney and Farber 1995).
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PMID:NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. 874 58

Supraspinal opioid analgesia is mediated in part by connections between the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Morphine analgesia elicited from the PAG is respectively decreased by selective serotonergic and opioid receptor antagonists administered into the RVM, and increased by RVM neurotensin antagonists. Since glutamate and excitatory amino acid (EAA) receptors are also active in the RVM, the present study evaluated whether either competitive (AP7) or non-competitive (MK-801) N-methyl-D-aspartate (NMDA) antagonists or a kainate/AMPA (CNQX) antagonist microinjected into the RVM altered morphine (2.5 micrograms) analgesia elicited from the PAG as measured by the tail-flick and jump tests. Mesencephalic morphine analgesia was markedly reduced on both tests after RVM pretreatment with either AP7 (0.01-1 microgram, 0.08-7.8 nmol) or MK-801 (0.03-3 micrograms, 0.04-4.4 nmol). In contrast, small but significant reductions in mesencephalic morphine analgesia occurred on the jump test following CNQX (0.5 microgram, 2.2 nmol) in the RVM. NMDA antagonists did not markedly alter either basal nociceptive thresholds following RVM administration, or mesencephalic morphine analgesia following administration into medullary placements lateral or dorsal to the RVM. These data implicate EAA and particularly NMDA receptors in the RVM in modulating the transmission of opioid pain-inhibitory signals from the PAG.
Pain 1996 Mar
PMID:Excitatory amino acid antagonists in the rostral ventromedial medulla inhibit mesencephalic morphine analgesia in rats. 878 20

The spinal cord dorsal horn contains neural mechanisms which can greatly facilitate pain. It is well established that excitatory amino acids, aspartate and glutamate, are involved in the spinal transmission of nociceptive information and in the development of hyperalgesia. In the present study, intrathecal (i.t.) administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), a structural analog of L-glutamate, produced a dose-dependent behavioural syndrome characterized by caudally directed biting in mice. We demonstrated that peripheral pre-administration of the AMPA receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX, 10-100 mg/kg s.c.) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3,4-dihydro-7, 8-methylene-dioxy-5H-2,3-benzo-diazepine-HCl (GYKI 53655, 3-10 mg/kg s.c.), and also of the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate (MK 801, 0.3-1 mg/kg s.c.) reversed this effect. These findings suggest that the hyperalgesia induced by the i.t. injection of AMPA in mice involves the activation of both NMDA and non-NMDA excitatory amino acid receptor sites.
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PMID:Pharmacological characterization of AMPA-induced biting behaviour in mice. 881 40

Recent studies indicate that glutamate binding to N-methyl-D-aspartate receptors in the spinal cord is involved in triggering the development of chronic pain However, the processes which directly underlie the increased pain remain unclear. Here we report that, following peripheral nerve injury (ligation of the sciatic nerve) in the rat, there is an increase in immunoreactive labelling of non-N-methyl-D-asparatate, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate), glutamate receptors in the superficial laminae of the lumbar spinal cord ipsilateral to the ligation. The increase in AMPA receptor expression peaks 14 days after nerve ligation and decreases 35 days post-ligation, corresponding to the time-course of heightened sensitivity to mechanical and thermal noxious stimuli (hyperalgesia) induced by the ligation. Given evidence that AMPA receptors in the superficial laminae mediate fast nociceptive transmission in the spinal cord, our findings suggest that an upregulation of spinal AMPA receptors contributes to hyperalgesia following peripheral nerve injury.
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PMID:Upregulation of spinal glutamate receptors in chronic pain. 884 72


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