The Spinal Antinociceptive Effect of Nocistatin in Neuropathic Rats Is Blocked by D-Serine

2004 ◽  
Vol 101 (3) ◽  
pp. 753-758 ◽  
Author(s):  
Uta Muth-Selbach ◽  
Eva Dybek ◽  
Katrin Kollosche ◽  
Jens-Ulrich Stegmann ◽  
Holger Holthusen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Antinociceptive Effect ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Antinociceptive Action ◽  
Glycine Release ◽  
Aspartate Receptor ◽  
Nociceptive Responses ◽  
High Doses

Background The neuropeptide nocistatin (NST) has been implicated in the modulation of nociceptive responses in the spinal cord. Depending on the dose, both pronociceptive and antinociceptive effects have repeatedly been reported. The pronociceptive effect is most likely attributable to inhibition of synaptic glycine and gamma-aminobutyric acid release and a subsequent reduction in the activation of inhibitory glycine and gamma-aminobutyric acid receptors, but the mechanisms of its antinociceptive action have hitherto remained elusive. It has recently been demonstrated that synaptically released glycine contributes to N-methyl-D-aspartate receptor activation. The authors therefore investigated whether a reduction in glycine release might also account for the antinociceptive action of NST in neuropathic rats. Methods The authors analyzed the effects of spinally applied NST in the chronic constriction injury model of neuropathic pain. NST was injected intrathecally from nanomolar to picomolar doses and its effects on thermal paw withdrawal latencies were monitored. Furthermore, we tested whether D-serine (100 microg per rat), a full agonist at the glycine binding site of the N-methyl-D-aspartate receptor, would interfere with the effects of NST. Results At high doses (10 nmol/rat), intrathecally injected NST was pronociceptive, whereas lower doses (1 pmol/rat) elicited antinociception. The antinociceptive, but not the pronociceptive, action was occluded by intrathecal pretreatment with D-serine. L-serine, which does not bind to N-methyl-D-aspartate receptors, affected neither the pronociceptive nor the antinociceptive effect. Conclusions These results demonstrate that NST produces a biphasic dose-dependent effect on neuropathic pain. The spinal antinociception by NST is most likely attributable to inhibition of glycine-dependent N-methyl-D-aspartate receptor activation.

scholarly journals The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

1999 ◽  
Vol 57 (3B) ◽  
pp. 753-760 ◽  
Author(s):  
TEREZINHA DE JESUS T. SANTOS ◽  
CARLOS M. DE CASTRO-COSTA ◽  
SÍLVIO D. A. GIFFONI ◽  
FRANKLIN J. C. SANTOS ◽  
RODRIGO S. N. RAMOS ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Aminobutyric Acid ◽  
Thermal Stimulus ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Analgesic Effects ◽  
Nociceptive Stimulus ◽  
Dose Dependent

Baclofen (beta-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p < 0.05) of scratching behaviour and significant increase (p < 0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.

Droperidol Inhibits GABAAand Neuronal Nicotinic Receptor Activation

2002 ◽  
Vol 96 (4) ◽  
pp. 987-993 ◽  
Author(s):  
Pamela Flood ◽  
Kristen M. Coates
Keyword(s):  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Hill Coefficient ◽  
High Dose ◽  
Gamma Aminobutyric Acid ◽  
Anesthetic Drugs ◽  
Gaba Inhibition ◽  
Acid Type ◽  
Anesthetic Action

Background Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors. Methods gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists. Results Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant. Conclusions Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.

scholarly journals A Conserved Tyrosine in the β2Subunit M4 Segment Is a Determinant of γ-Aminobutyric Acid Type A Receptor Sensitivity to Propofol

2007 ◽  
Vol 107 (3) ◽  
pp. 412-418 ◽  
Author(s):  
James E. Richardson ◽  
Paul S. Garcia ◽  
Kate K. O'Toole ◽  
Jason M. C. Derry ◽  
Shannon V. Bell ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetics ◽  
Receptor Function ◽  
293 Cells ◽  
Acid Type ◽  
Normal Sensitivity

Background The gamma-aminobutyric acid type A receptor (GABAA-R) beta subunits are critical targets for the actions for several intravenous general anesthetics, but the precise nature of the anesthetic binding sites are unknown. In addition, little is known about the role the fourth transmembrane (M4) segment of the receptor plays in receptor function. The aim of this study was to better define the propofol binding site on the GABAA-R by conducting a tryptophan scan in the M4 segment of the beta2 subunit. Methods Seven tryptophan mutations were introduced into the C-terminal end of the M4 segment of the GABAA-R beta2 subunit. GABAA-R subunit complementary DNAs were transfected into human embryonic kidney 293 cells grown on glass coverslips. After transfection (36-72 h), coverslips were transferred to a perfusion chamber to assay receptor function. Cells were whole cell patch clamped and exposed to GABA, propofol, etomidate, and pregnenolone. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. Results All tryptophan mutations were well tolerated, and with one exception, all resulted in minimal changes in receptor activation by GABA. One mutation, beta2(Y444W), selectively suppressed the ability of propofol to enhance receptor function while retaining normal sensitivity to etomidate and pregnenolone. Conclusions This is the first report of a mutation that selectively reduces propofol sensitivity without altering the action of etomidate. The reduction in propofol sensitivity is consistent with the loss of a hydrogen bond within the propofol binding site. These results also suggest a possible orientation of the propofol molecule within its binding site.

Regulation of endogenous dopamine release in amphibian retina by gamma-aminobutyric acid and glycine

1994 ◽  
Vol 11 (5) ◽  
pp. 1003-1012 ◽  
Author(s):  
Jeffrey H. Boatright ◽  
Nara M. Rubim ◽  
P. Michael Iuvone
Keyword(s):  
Receptor Agonist ◽  
Dopamine Release ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Endogenous Dopamine ◽  
Endogenous Dopamine Release ◽  
Inhibitory Tone

AbstractEndogenous dopamine release in the retina of the African clawed frog (Xenopus laevis) increases in light and decreases in darkness. The roles of the inhibitory amino acid transmitters gamma-aminobutyric acid (GABA) and glycine in regulating this light/dark difference in dopamine release were explored in the present study. Exogenous GABA, the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, and the GABA-C receptor agonist cis-aminocrotonic acid (CACA) suppressed light-evoked dopamine overflow from eyecups. The effects of GABA-A and -B receptor agonists were selectively reversed by their respective receptor-specific antagonists, whereas the effect of CACA was reversed by the competitive GABA-A receptor antagonist bicuculline. The benzodiazepine diazepam enhanced the effect of muscimol on light-evoked dopamine release. Both GABA-A and -B receptor antagonists stimulated dopamine release in light or darkness. Bicuculline was more potent in light than in darkness. These data suggest that retinal dopaminergic neurons are inhibited by GABA-A and -B receptor activation in both light and darkness but that GABA-mediated inhibitory tone may be greater in darkness than in light.Exogenous glycine inhibited light-stimulated dopamine release in a concentration-dependent and strychnine-sensitive manner. However, strychnine alone did not increase dopamine release in light or darkness, nor did it augment bicuculline-stimulated release in darkness. Additionally, both strychnine and 7-chlorokynurenate, an antagonist of the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate subtype of glutamate receptor, suppressed light-evoked dopamine release. Thus, the role of endogenous glycine in the regulation of dopamine release remains unclear.

Brain Stem Opioidergic and GABAergic Neurons Mediate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats

2003 ◽  
Vol 99 (4) ◽  
pp. 947-954 ◽  
Author(s):  
Yoko Ohashi ◽  
Tianzhi Guo ◽  
Ryo Orii ◽  
Mervyn Maze ◽  
Masahiko Fujinaga
Keyword(s):  
Spinal Cord ◽  
Brain Stem ◽  
Antinociceptive Effect ◽  
Opioid Peptide ◽  
Periaqueductal Gray ◽  
Gabaergic Neurons ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Gray Area ◽  
Fos Expression

Background Recent studies have revealed that N2O exerts its antinociceptive effect by inducing opioid peptide release in the brain stem, thereby activating the descending noradrenergic inhibitory neurons, which modulate pain processing in the spinal cord. However, the precise neuronal pathways that mediate these events remain to be determined. Methods Using immunohistochemical and behavioral techniques in adult male Fischer rats, the authors studied the involvement of brain stem opioidergic and gamma-aminobutyric acid-mediated (GABAergic) neurons in the N2O-induced antinociceptive effect using discrete microinjections of an opioid receptor antagonist or GABAergic activator into the periaqueductal gray area and pontine noradrenergic nuclei. They used c-Fos expression as an immunohistochemical mark of neuronal activation induced by N2O and the plantar test as the behavioral paradigm for nociception. Results Microinjection of either naloxone (an opioid receptor antagonist) or muscimol (a gamma-aminobutyric acid receptor type A agonist) into the ventrolateral periaqueductal gray area inhibited N2O-induced c-Fos expression in the spinal cord and pontine noradrenergic nuclei, particularly in the A7. Microinjection of either naloxone or muscimol into the A7 nuclei also inhibited N2O-induced c-Fos expression in the spinal cord and the N2O-induced antinociceptive effect by the plantar test. Conclusions These results support the hypothesis that both opioidergic and GABAergic neurons mediate the antinociceptive effect of N2O at the periaqueductal gray area and A7 in the brain stem. The authors postulate that N2O-induced opioid peptide release leads to inhibition of GABAergic neurons via opioid receptors. The descending noradrenergic inhibitory pathways, which are tonically inhibited by these gamma-aminobutyric acid neurons, are thereby activated (disinhibited) and modulate pain processing in the spinal cord.

The Antinociceptive Effect of SNAP5114, a Gamma-Aminobutyric Acid Transporter-3 Inhibitor, in Rat Experimental Pain Models

2013 ◽  
Vol 116 (5) ◽  
pp. 1162-1169 ◽  
Author(s):  
Kazunori Kataoka ◽  
Koji Hara ◽  
Yasunori Haranishi ◽  
Tadanori Terada ◽  
Takeyoshi Sata
Keyword(s):  
Antinociceptive Effect ◽  
Experimental Pain ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Pain Models ◽  
Acid Transporter

Only Early Intervention with Gamma-Aminobutyric Acid Cell Therapy Is Able to Reverse Neuropathic Pain After Partial Nerve Injury

2001 ◽  
Vol 18 (4) ◽  
pp. 471-477 ◽  
Author(s):  
Leigh Ann Stubley ◽  
Miguel A. Martinez ◽  
Shaffiat Karmally ◽  
Tomas Lopez ◽  
Pedro Cejas ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Early Intervention ◽  
Cell Therapy ◽  
Nerve Injury ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid

scholarly journals Rituximab for Autoimmune Encephalitis with Epilepsy

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Mohankumar Kurukumbi ◽  
Rahul H. Dave ◽  
Jose Castillo ◽  
Tulsi Shah ◽  
Joanne Lau
Keyword(s):  
Intractable Epilepsy ◽  
Autoimmune Encephalitis ◽  
Aminobutyric Acid ◽  
High Dose ◽  
Gamma Aminobutyric Acid ◽  
Acid Receptor ◽  
Voltage Gated ◽  
Aspartate Receptor ◽  
A Cell

Intractable epilepsy remains a significant medical challenge, resulting in recurrent and prolonged intensive care unit (ICU) admissions. Autoimmune encephalitis is emerging as a treatable cause of intractable epilepsy. It is characterized by antibodies against cerebral antigens, such as potassium channels such as leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2), calcium channels such as the voltage-gated calcium channel (VGCC), or neurotransmitter receptors such as the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma aminobutyric acid receptor (GABAR), and N-methyl-D-aspartate receptor (NMDAR). Diagnosis requires a syndrome consistent with an antibody identified in serum or cerebrospinal fluid (CSF) using methods that minimize risk of false-positives. Although there is no officially approved therapy for these disorders, typical approaches involve chronic high-dose steroids, intravenous immunoglobulin (IVIG), or plasma exchange. Rituximab is effective for antibody-associated disorders such as lupus, myasthenia gravis, and neuromyelitis optica. Here, we present three patients who were admitted with recalcitrant status epilepticus and demonstrated serum antibodies against NMDAR, LGI1, or VGCC using a cell-based assay. All patients demonstrated complete, long-term epilepsy control and improvement in symptoms with rituximab.

Inhibition of transmitter release shortens the duration of the excitatory synaptic current at a calyceal synapse

1996 ◽  
Vol 76 (5) ◽  
pp. 3584-3588 ◽  
Author(s):  
T. S. Otis ◽  
L. O. Trussell
Keyword(s):  
Transmitter Release ◽  
Time Course ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Synaptic Currents ◽  
Quantal Release ◽  
Epsc Amplitude ◽  
Gabaa Receptor Antagonist

1. We investigated the effect of reducing transmitter release on the time course of multiquantal, evoked synaptic currents to test for transmitter “cross talk” between neighboring synaptic release sites within a calyceal synapse. By using a brain slice preparation, neurons in the chick nucleus magnocellularis (nMAG) were voltage clamped and individual presynaptic axons were stimulated to evoke excitatory postsynaptic currents (EPSCs). 2. Application of 100-microM baclofen or 50-microM GABA in the presence of a gamma-aminobutyric acid-A (GABAA) receptor antagonist produced an 85% reduction of EPSCs, consistent with the activation of presynaptic gamma-aminobutyric acid-B (GABAB) receptors. In parallel with the reduction in the amplitude of the EPSC by GABAB receptor activation, the normally strong paired pulse depression (PPD) of the EPSC was converted to facilitation. The reduction in EPSC amplitude by gamma-aminobutyric acid (GABA) or baclofen was accompanied by a 20% reduction in the exponential time constant of decay of the EPSC. Weaker effects on the EPSC time course were observed for synapses with the least PPD. 3. Cd2+ (5 microM), which inhibits presynaptic calcium current, also reduced EPSC amplitude by 85% and converted PPD to facilitation. EPSCs were narrower in Cd2+, though less so than in baclofen. 4. The time course of the EPSC was longer than that of miniature synaptic currents, even after significant block by baclofen, GABA or Cd2+, indicating that dispersion of quantal release may help shape the synaptic waveform. However, the narrowing of the EPSC by baclofen, GABA, and Cd2+ suggests that high levels of quantal release at the calyceal synapse may delay the removal of transmitter, further slowing the EPSC.

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