Analgesic Interaction between Intrathecal Midazolam and Glutamate Receptor Antagonists on Thermal-induced Pain in Rats 

1999 ◽  
Vol 91 (2) ◽  
pp. 531-537 ◽  
Author(s):  
Tomoki Nishiyama ◽  
Laszlo Gyermek ◽  
Chingmuh Lee ◽  
Sachiko Kawasaki-Yatsugi ◽  
Tokio Yamaguchi
Keyword(s):  
Receptor Antagonist ◽  
Glutamate Receptor ◽  
Ampa Receptor ◽  
Behavioral Changes ◽  
Tail Flick ◽  
Receptor Antagonists ◽  
Thermal Nociception ◽  
Motor Disturbance ◽  
Ampa Receptor Antagonist ◽  
Glutamate Receptor Antagonists

Background Two major neurotransmitters, gamma-aminobutyric acid (GABA) and the excitatory amino acid, glutamate, may be involved in nociception in the spinal cord. GABA and glutamate receptors may operate in concert to modify signals in the central nervous system. The purpose of this study was to investigate the spinal analgesic interaction between midazolam, a benzodiazepine-GABA(A) receptor agonist, and two glutamate receptor antagonists on acute thermal nociception. Methods Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters and were tested for their tail withdrawal response by the tail flick test after intrathecal administration of saline, midazolam (1-100 microg), AP-5 (1-30 microg), or YM872 (0.3-30 microg). AP-5 is an N-methyl-D-aspartate (NMDA) receptor antagonist and YM872 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. The combination of midazolam and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed. Results Dose-dependent increases in the tail flick latency were observed with midazolam, AP-5, and YM872 with 50% effective dose values of 1.57+/-0.34 (SEM) microg, 5.54+/-0.19 microg, and 1.0+/-0.22 microg, respectively. A potent synergy in analgesia with decreased behavioral changes and motor disturbance was obtained when combining midazolam with AP-5 or YM872. Conclusions Spinally administered midazolam and an NMDA- or an AMPA-receptor antagonist exhibited potent synergistic analgesia on acute thermal nociception in rats. Side effects, shown by behavioral changes and motor disturbance, decreased with the combination of the agents. These results point out an important direction for the study of acute nociception.

Glutamate Receptor Antagonists Block Gustatory Afferent Input to the Nucleus of the Solitary Tract

1997 ◽  
Vol 77 (3) ◽  
pp. 1514-1525 ◽  
Author(s):  
Cheng-Shu Li ◽  
David V. Smith
Keyword(s):  
Receptor Antagonist ◽  
Glutamate Receptor ◽  
Drug Administration ◽  
Afferent Input ◽  
Chemical Stimulation ◽  
Kainate Receptor ◽  
Solitary Tract ◽  
Receptor Antagonists ◽  
Glutamate Receptor Antagonists ◽  
Stimulation Of

Li, Cheng-Shu and David V. Smith. Glutamate receptor antagonists block gustatory afferent input to the nucleus of the solitary tract. J. Neurophysiol. 77: 1514–1525, 1997. The effects of excitatory amino acid (EAA) receptor antagonists in blocking the synaptic transmission between gustatory fibers of the chorda tympani (CT) nerve and taste-responsive neurons within the nucleus of the solitary tract (NST) were examined electrophysiologically in urethan-anesthetized hamsters. Single neurons in the NST were recorded extracellularly and drugs were microinjected into the vicinity of the cell with the use of a multibarrel pipette assembly. The activity of each cell was recorded in response to lingual stimulation with 0.032 M NaCl, 0.032 M sucrose, 0.0032 M citric acid, 0.032 M quinine hydrochloride, and/or 25-μA anodal current pulses. Once a cell was identified as a taste-responsive neuron, one or more EAA receptor antagonists were administered by microinjection. Approximately 27 nl of 50 mM kynurenic acid (KYN), a broad-spectrum EAA receptor antagonist; 0.5 or 2.0 mM dl-2-amino-5-phosphonovalerate (APV), an N-methyl-d-aspartate (NMDA) receptor antagonist; 0.05 or 0.5 mM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist; or phosphate-buffered physiological saline was applied to the neuron. Responses to chemical stimulation of the anterior tongue were obtained before and after drug administration and again after recovery; responses to anodal current stimulation (0.1 Hz) were obtained continually throughout the drug administration protocol. Microinjection of KYN completely and reversibly abolished responses elicited by both anodal current and chemical stimulation of the anterior tongue. The excitatory responses of cells in the NST to chemical and electrical stimulation of the anterior tongue were also completely and reversibly blocked by CNQX, implicating the involvement of an AMPA/kainate receptor. Microinjection of APV was generally less effective and partially reduced the responses of some taste-responsive NST cells to chemical stimulation of the anterior tongue. There were no effects following microinjection of a 27-nl bolus of phosphate-buffered saline. None of these EAA receptor antagonists had a differential effect on responses to different taste stimuli. The responses to all tastants were completely blocked by both KYN and CNQX; there was no apparent relationship between the response to any particular tastant and the limited effects of APV. These data implicate glutamate as an excitatory neurotransmitter between CT gustatory fibers and taste-responsive NST cells and suggest that it acts primarily on AMPA/kainate receptors, with some contribution from NMDA receptors. This conclusion is strengthened by other data obtained from in vitro slice preparations, which show that responses of cells in the rostral NST to solitary tract stimulation are blocked by both NMDA and AMPA/kainate receptor antagonists.

Glutamatergic and GABAergic Regulation of Neural Responses in Inferior Colliculus to Amplitude-Modulated Sounds

2003 ◽  
Vol 90 (1) ◽  
pp. 477-490 ◽  
Author(s):  
Huiming Zhang ◽  
Jack B. Kelly
Keyword(s):  
Firing Rate ◽  
Receptor Antagonist ◽  
Inferior Colliculus ◽  
Ampa Receptor ◽  
Transfer Functions ◽  
Modulation Frequency ◽  
Modulation Transfer ◽  
Neural Responses ◽  
Receptor Antagonists ◽  
Ampa Receptor Antagonist

Recordings were made from single neurons in the rat inferior colliculus in response to sinusoidally amplitude-modulated sounds (10-s duration) presented to the contralateral ear. Neural responses were determined for different rates of modulation (0.5 Hz to 1 kHz) at a depth of 100%, and modulation transfer functions were generated based on firing rate (MTFFR) and vector strength (MTFVS). The effects of AMPA, NMDA, and GABAA receptor antagonists were examined by releasing drugs iontophoretically through a multibarrel pipette attached to a single-barrel recording pipette. Both the AMPA receptor antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX), and the NMDA receptor antagonist, (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) resulted in a decrease in firing rate, and the GABAA receptor antagonist, bicuculline, produced an increase in the firing rate in most of the cells examined. In some cases, the shape of the MTFFR was modified slightly by receptor antagonists, but in most cases, the peak firing rate that determined a neuron's best modulation frequency remained the same. Also there were no changes during delivery of either excitatory or inhibitory antagonists in the maximum response synchrony at the peak of the MTFVS although some changes were noticed at off-peak modulation rates particularly with the AMPA receptor antagonist, NBQX.

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

The Analgesic Interaction Between Intrathecal Clonidine and Glutamate Receptor Antagonists on Thermal and Formalin-Induced Pain in Rats

2001 ◽  
pp. 725-732 ◽  
Author(s):  
Tomoki Nishiyama ◽  
Laszlo Gyermek ◽  
Chingmuh Lee ◽  
Sachiko Kawasaki-Yatsugi ◽  
Tokio Yamaguchi ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Receptor Antagonists ◽  
Glutamate Receptor Antagonists ◽  
Intrathecal Clonidine

Structural Determinants of the γ-8 TARP Dependent AMPA Receptor Antagonist

2017 ◽  
Vol 8 (12) ◽  
pp. 2631-2647 ◽  
Author(s):  
Matthew R. Lee ◽  
Kevin M. Gardinier ◽  
Douglas L. Gernert ◽  
Douglas A. Schober ◽  
Rebecca A. Wright ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Structural Determinants ◽  
Ampa Receptor Antagonist
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