Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spreading depression (SD) is a profound but transient depolarization of neurons and glia that migrates across the cortical and subcortical gray at 2-5 mm/min. Under normoxic conditions, SD occurs during migraine aura where it precedes migraine pain but does not damage tissue. During stroke and head trauma, however, SD can arise repeatedly near the site of injury and may promote neuronal damage. We developed a superfused brain slice preparation that can repeatedly support robust SD during imaging and electrophysiological recording to test drugs that may block SD. Submerged rat neocortical slices were briefly exposed to artificial cerebrospinal fluid (ACSF) with KCl elevated to 26 mM. SD was evoked within 2 min, recorded in layers II/III both as a negative DC shift and as a propagating front of elevated light transmittance (LT) representing transient cell swelling in all cortical layers. An SD episode was initiated focally and could be repeatedly evoked and imaged with no damage to slices. As reported in vivo, pretreatment with one of several N-methyl-D-aspartate (NMDA) receptor antagonists blocked SD, but a non-NMDA glutamate receptor antagonist (CNQX) had no effect. NMDA receptor (NMDAR) activation does not initiate SD nor are NMDAR antagonists tolerated therapeutically so we searched for more efficacious drugs to block SD generation. Pretreatment with the sigma-one receptor (sigma(1)R) agonists dextromethorphan (10-100 microM), carbetapentane (100 microM), or 4-IBP (30 microM) blocked SD, even when KCl exposure was extended beyond 5 min. The block was independent of NMDA receptor antagonism. Two sigma(1)R antagonists [(+)-3PPP and BD-1063] removed this block but had no effect upon SD alone. Remarkably, the sigma(1)R agonists also substantially reduced general cell swelling evoked by bath application of 26 mM KCl. More potent sigma(1)R ligands that are therapeutically tolerated could prove useful in reducing SD associated with migraine and be of potential use in stroke or head trauma.
 ...
PMID:Spreading depression: imaging and blockade in the rat neocortical brain slice. 1242 6

Acute nociceptive, inflammatory, and neuropathic pain all depend to some degree on the peripheral activation of primary sensory afferent neurons. The localized peripheral administration of drugs, such as by topical application, can potentially optimize drug concentrations at the site of origin of the pain, while leading to lower systemic levels and fewer adverse systemic effects, fewer drug interactions, and no need to titrate doses into a therapeutic range compared with systemic administration. Primary sensory afferent neurons can be activated by a range of inflammatory mediators such as prostanoids, bradykinin, ATP, histamine, and serotonin, and inhibiting their actions represents a strategy for the development of analgesics. Peripheral nerve endings also express a variety of inhibitory neuroreceptors such as opioid, alpha-adrenergic, cholinergic, adenosine and cannabinoid receptors, and agonists for these receptors also represent viable targets for drug development. At present, topical and other forms of peripheral administration of nonsteroidal anti-inflammatory drugs, opioids, capsaicin, local anesthetics, and alpha-adrenoceptor agonists are being used in a variety of clinical states. There also are some clinical data on the use of topical antidepressants and glutamate receptor antagonists. There are preclinical data supporting the potential for development of local formulations of adenosine agonists, cannabinoid agonists, cholinergic ligands, cytokine antagonists, bradykinin antagonists, ATP antagonists, biogenic amine antagonists, neuropeptide antagonists, and agents that alter the availability of nerve growth factor. Given that activation of sensory neurons involves multiple mediators, combinations of agents targeting different mechanisms may be particularly useful. Topical analgesics represent a promising area for future drug development.
 ...
PMID:Topical and peripherally acting analgesics. 1261 51

Glutamate neurotransmission plays an important role in the processing of pain and in chronic opioid-induced neural and behavioral plasticity, such as opioid withdrawal and opioid dependence. Kappa-opioid receptors also have been implicated in acute opioid modulation of pain and chronic opioid-induced plasticity, both of which are primarily mediated by mu-opioid receptors. Using whole-cell patch clamp recordings in brain slices in vitro and system analysis of pain behaviors in rats in vivo, this study investigated the functional role of glutamate synaptic transmission and kappa-opioid receptors in two behavioral pain conditions: m-opioid-induced analgesia (decreased pain) and mu-opioid withdrawal-induced hyperalgesia (increased pain). In the nucleus raphe magnus (NRM), a brainstem structure that controls spinal pain transmission, we found that kappa-receptor agonists presynaptically inhibited glutamate synaptic currents in both of the two cell types that are thought to respectively inhibit or facilitate spinal pain transmission. In rats, both glutamate receptor antagonists and the kappa agonist microinjected into the NRM attenuated mu-opioid-induced analgesia, which is most likely mediated through activation of such pain-inhibiting neurons. However, during opioid abstinence-induced withdrawal, the same doses of glutamate receptor antagonists and the kappa agonist administered in the NRM suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal. These results demonstrate that kappa-opioid receptors antagonize mu-receptor-induced effects in both analgesic and hyperalgesic states, and suggest inhibition of glutamate synaptic transmission as a presynaptic mechanism for the kappa antagonism of these two mu receptor-mediated actions.
 ...
PMID:Presynaptic mechanism for anti-analgesic and anti-hyperalgesic actions of kappa-opioid receptors. 1291 59

Glutamate is the most important excitatory transmitter in the central nervous system. A tremendous complexity in the actions of this excitatory transmitter was found and an equally great complexity in the molecular structures of the receptors activated by glutamate. The glutamate receptor system influences nearly all other neurotransmitter systems. Glutamate also plays a central role in important processes of the central nervous system like the long-term potentiation in the hippocampus and the central sensitization for pain stimuli in the spinal cord, which is predominantly mediated by NMDA-receptors. But there are actions of glutamate beyond its function as an excitatory transmitter. Glutamate also has a trophic influence on neurons--depending upon the developmental stage. The excitotoxicity of glutamate mediated by NMDA-receptors is the common ultimate mechanism of acute and chronic nerve cell death and plays an important role in many acute neurologic diseases. The modulation of the glutamate system for example by antagonist of the glutamate-receptors might be a possible way in therapy of many different diseases of the central nervous system.
 ...
PMID:[Glutamate--a transmitter in the tensionfield between toxin and trophine]. 1294 37

Glutamate receptors are implicated in many actions in the central nervous system, as an excitatory amino acid, and one of the more relevant is its role in excitotoxicity. Apart from this, it also has a role as pro-nociceptive agent, so that antagonizing its actions could be of interest for developing new analgesic agents. Furthermore, between the analgesics agents, it is of outstanding interest the fact that there is no specific therapy against the neuropathic pain, and glutamate receptor subunits have elicited as new potential targets for this disturbance.
 ...
PMID:AMPA glutamate receptors and neuropathic pain. 1452 16

Adenosine can reduce pain and allodynia in animals and man, probably via spinal adenosine A1 receptors. In the present study, we investigate the distribution of the adenosine A1 receptor in the rat spinal cord dorsal horn using immunohistochemistry, in situ hybridization, radioligand binding, and confocal microscopy. In the lumbar cord dorsal horn, dense immunoreactivity was seen in the inner part of lamina II. This was unaltered by dorsal root section or thoracic cord hemisection. Confocal microscopy of the dorsal horn revealed close anatomical relationships but no or only minor overlap between A1 receptors and immunoreactivity for markers associated with primary afferent central endings: calcitonin gene-related peptide, or isolectin B4, or with neuronal subpopulations: mu-opioid receptor, neuronal nitric oxide synthase, met-enkephalin, parvalbumin, or protein kinase Cgamma, or with glial cells: glial fibrillary acidic protein. A few adenosine A1 receptor positive structures were double-labeled with alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionic acid glutamate receptor subunits 1 and 2/3. The results indicate that most of the adenosine A1 receptors in the dorsal horn are located in inner lamina II postsynaptic neuronal cell bodies and processes whose functional and neurochemical identity is so far unknown. Many adenosine A1 receptor positive structures are in close contact with isolectin B4 positive C-fiber primary afferents and/or postsynaptic structures containing components of importance for the modulation of nociceptive information.
 ...
PMID:Distribution of antinociceptive adenosine A1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations. 1458 Sep 41

Sequencing of the human, mouse, and rat genomes has enabled a comprehensive informatics approach to gene families. This approach is informative for identification of new members of gene families, for cross-species sequence conservation related to functional conservation, for within-species diversity related to functional variation, and for historical effects of selection. This genome informatics approach also focuses our attention on genes whose genomic locations coincide with linkages to phenotypes. We are identifying ionotropic glutamate receptor (IGR) sequence variation by resequencing technologies, including denaturing high-performance liquid chromoatography (dHPLC), for screening and direct sequencing, and by information mining of public (e.g., dbSNP and ENSEMBL) and private (i.e., Celera Discovery System) sequence databases. Each of the 16 known IGRs is represented in these databases, their positions on a canonical physical map (for example, the Celera map) are established, and comparison to mouse and rat sequences has been performed, revealing substantial conservation of these genes, which are located on different chromosomes but found within syntenic groups of genes. A collection of 38 missense variants were identified by the informatics and resequencing approaches in several of these receptor genes, including GRIN2B, GRIN3B, GRIA2, GRIA3, and GRIK1. This represents only a fraction of the sequence variation across these genes, but, in fact, these may constitute a large fraction of the common polymorphisms at these genes, and these polymorphisms are a starting point for understanding the role of these receptors in neurogenetic variation. Genetically influenced human neurobehavioral phenotypes that are likely to be linked to IGR genetic variants include addictions, anxiety/dysphoria disorders, post-brain injury behavioral disorders, schizophrenia, epilepsy, pain perception, learning, and cognition. Thus, the effects of glutamate receptor variation may be protean, and the task of relating variation to behavior difficult. However, functional variants of (1) catechol-O-methyltransferase, (2) serotonin transporter, and (3) brain-derived neurotrophic factor have recently been linked both to behavioral differences and to intermediate phenotypes, suggesting a pathway by which functional variation at IGRs can be tied to an etiologically complex phenotype.
 ...
PMID:Genomics and variation of ionotropic glutamate receptors. 1468 33

The aim of this study was to determine the influence of a glutamate receptor antagonist or a protein kinase C (PKC) inhibitor on the central visceral nociceptive amplification process present in an experimental pancreatitis model. The acute pancreatitis model was produced by combining intraductal infusion of an irritative bile salt, glycodeoxycholic acid (GDOC), with intraperitoneal injection of a CCK analogue, caerulein, in male Sprague-Dawley rats. Exploratory activities were measured with an automated photobeam activity system and compared among different treatment groups. To confirm the inflammation, the pancreas was weighed and compared histologically with those taken from naive rats. Exploratory activity changed significantly in rats with experimental pancreatitis (i.e., rearing events, rearing time, active time, distance traveled, and total activity all were decreased; whereas resting time was increased). The inflamed pancreatic tissues were edematous, with moderate to marked acinar atrophy and inflammatory infiltrate. Intrathecal administration (at the T7-T9 spinal levels) of an NMDA receptor antagonist (D-AP5, 1 microg) or a selective PKC inhibitor (GF109203X, 0.15 microg) significantly reversed the changes in exploratory activity when compared with the vehicle-treated group of rats with experimental pancreatitis. Our results demonstrate that pancreatitis pain is the result of central pain processes that play a role in the amplification of responses to peripheral visceral input through NMDA receptor activation and PKC phosphorylation signaling pathways.
 ...
PMID:Restoration of spontaneous exploratory behaviors with an intrathecal NMDA receptor antagonist or a PKC inhibitor in rats with acute pancreatitis. 1472 52

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and is critical for essentially all physiological processes ranging from control of motor and somatosensory function to information processing and storage. Like many other small molecule neurotransmitters, transporters localized to the plasma membrane control the extracellular concentrations of glutamate. These transporters are both acutely and chronically regulated by several different mechanisms that presumably contribute to the protection of the nervous system from hypo- or hyper-glutamatergic function. In this review, we will describe our emerging understanding of one aspect of glutamate transporter regulation that is dependent on protein kinase C. More than a decade of extensive research on glutamate receptor-specific therapeutics has been driven by the hypothesis that these agents might be useful for pain management, treatment of schizophrenia or other psychiatric disorders, and prevention of neurodegenerative diseases. We assume that, in this modern era of drug discovery, understanding the endogenous regulatory mechanisms that are activated under physiological and pathological conditions will be required before one can target transporters for a ubiquitous neurotransmitter like glutamate.
 ...
PMID:Protein kinase C-dependent remodeling of glutamate transporter function. 1499 76

Previous studies have shown that repeated injections of acidic saline, given into the lateral gastrocnemius muscle of rats, results in a bilateral reduction in withdrawal threshold to tactile stimulation of the hindpaws. We have now characterised this model of muscoskeletal pain pharmacologically, by evaluating the antinociceptive effects of various analgesics after systemic administration. The micro-opioid receptor agonist morphine (3 and 6 mg/kg) produced a particularly prolonged antiallodynic effect. The glutamate receptor antagonists ([8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-iso-quinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime] NS1209 and ketamine (6 and 15 mg/kg, respectively), the KCNQ K(+) channel openers retigabine and flupirtine (10 and 20 mg/kg, respectively) and the Na(+) channel blocker mexiletine (37.5 mg/kg) also significantly increased paw withdrawal threshold, although to a lesser degree than morphine. In contrast, the anticonvulsant lamotrigine (30 mg/kg), the cyclooxygenase-2 inhibitor carprofen (15 mg/kg) and the benzodiazepine diazepam (3 mg/kg) were ineffective. All antinociceptive effects were observed at nonataxic doses as determined by the rotarod test. These results suggest that in this model, muscle-mediated pain can be alleviated by various analgesics with differing mechanisms of action, and that once established ongoing inflammation does not appear to contribute to this process.
 ...
PMID:Pharmacological characterisation of acid-induced muscle allodynia in rats. 1503 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>