GABAergic Interneurons at Supraspinal and Spinal Levels Differentially Modulate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats

2003 ◽  
Vol 98 (5) ◽  
pp. 1223-1230 ◽  
Author(s):  
Ryo Orii ◽  
Yoko Ohashi ◽  
Sunil Halder ◽  
Mariangela Giombini ◽  
Mervyn Maze ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Antinociceptive Effect ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Fischer Rats ◽  
The Brain ◽  
Gas Exposure

Background The study hypothesizes that nitrous oxide (N(2)O) releases opioid peptide in the brain stem, which results in inhibition of gamma-aminobutyric acid-mediated (GABAergic) neurons that tonically inhibit the descending noradrenergic inhibitory neurons (DNIN), resulting in activation of DNIN. In the spinal cord, activation of DNIN leads to the release of norepinephrine, which inhibits nociceptive processing through direct activation of alpha2 adrenoceptor and indirect activation of GABAergic neurons through alpha1 adrenoceptor. Arising from this hypothesis, it follows that GABAergic neurons will modulate the antinociceptive effect of N(2)O in diametrically opposite directions at supraspinal and spinal levels. The authors have tested this tenet and further examined the effect of midazolam, a GABA-mimetic agent, on N(2)O-induced antinociceptive effect. Methods Adult male Fischer rats were administered muscimol (GABA(A) receptor agonist) intracerebroventricularly (icv), gabazine (GABA(A) receptor antagonist) intrathecally (intrathecal), or midazolam intraperitoneally (intraperitoneal). Fifteen minutes later, they were exposed to air or 75% N(2)O and were subjected to the plantar test after 30 min of gas exposure. In some animals administered with midazolam, gas exposure was continued for 90 min, and the brain and spinal cord were examined immunohistochemically. Results The N(2)O-induced antinociceptive effect, which was attenuated by icv muscimol, intrathecal gabazine, and intraperitoneal midazolam. Midazolam inhibited N(2)O-induced c-Fos expression (a marker of neuronal activation) in the pontine A7 and spinal cord. Conclusions The GABAergic neurons modulate the antinociceptive effect of N(2)O in opposite directions at supraspinal and spinal levels. The pronociceptive effects of enhancement at the supraspinal GABAergic site predominate in response to systemically administered midazolam.

Nitrous Oxide Activates GABAergic Neurons in the Spinal Cord in Fischer Rats

2001 ◽  
Vol 95 (2) ◽  
pp. 463-469 ◽  
Author(s):  
Toshikazu Hashimoto ◽  
Mervyn Maze ◽  
Yoko Ohashi ◽  
Masahiko Fujinaga
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Antinociceptive Effect ◽  
Gabaergic Neurons ◽  
Acid Decarboxylase ◽  
Noradrenergic Neurons ◽  
Neuronal Activation ◽  
Fischer Rats

Background Findings to date indicate that nitrous oxide exerts its antinociceptive effect by activating descending noradrenergic neurons. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociceptive effect remains unclear. Using c-Fos protein as a marker for neuronal activation, we examined whether spinal cord neurons activated by nitrous oxide are y-aminobutyric acid-mediated (GABAergic) neurons. Methods Adult male Fischer (a strain in which nitrous oxide shows strong antinociceptive properties) and Lewis (a strain in which nitrous oxide lacks antinociceptive properties) rats were exposed to either air (control) or nitrous oxide. Frozen sections of the spinal cord were either stained for c-Fos or double-stained for c-Fos and glutamic acid decarboxylase (a rate-limiting enzyme for GABA synthesis) and analyzed by standard or confocal microscopy. Results In Fischer rats, 90 min of 75% N2O administration increased the number of c-Fos-positive cells in the spinal cord approximately threefold as compared with the control group. The c-Fos-positive cells induced by nitrous oxide were almost entirely colocalized with glutamic acid decarboxylase-positive cells. In contrast, exposure did not change the number of c-Fos-positive cells in the spinal cord in Lewis rats. Conclusions Exposure to nitrous oxide activates GABAergic neurons in the spinal cord. The dose-dependence of GABAergic neuronal activation in the Fischer rats and its absence in the Lewis rat correlate with antinociceptive responses previously reported in these same circumstances. Together, we interpret these data to indicate that activation of GABAergic neurons in the spinal cord are involved in the antinociceptive action of nitrous oxide.

Evidence for the Involvement of Spinal Cord α1Adrenoceptors in Nitrous Oxide–induced Antinociceptive Effects in Fischer Rats

2002 ◽  
Vol 97 (6) ◽  
pp. 1458-1465 ◽  
Author(s):  
Ryo Orii ◽  
Yoko Ohashi ◽  
Tianzhi Guo ◽  
Laura E. Nelson ◽  
Toshikazu Hashimoto ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Receptor Antagonist ◽  
Serotonin Receptor ◽  
Antinociceptive Effect ◽  
Gabaergic Neurons ◽  
Adrenoceptor Antagonist ◽  
Fischer Rats ◽  
Fos Expression ◽  
Alpha2 Adrenoceptor

Background In a previous study, the authors found that nitrous oxide (N2O) exposure induces c-Fos (an immunohistochemical marker of neuronal activation) in spinal cord gamma-aminobutyric acid-mediated (GABAergic) neurons in Fischer rats. In this study, the authors sought evidence for the involvement of alpha1 adrenoceptors in the antinociceptive effect of N2O and in activation of GABAergic neurons in the spinal cord. Methods Adult male Fischer rats were injected intraperitoneally with alpha1 adrenoceptor antagonist, alpha2 adrenoceptor antagonist, opioid receptor antagonist, or serotonin receptor antagonist and, 15 min later, were exposed to either air (control) or 75% N2O. In some animals, nociception was investigated with the plantar test after 30 min of exposure, while in other animals, gas exposure was continued for 90 min and the spinal cord was examined for c-Fos immunostaining. In a separate experiment, animals were exposed to the above gases alone, after which the spinal cords were examined immunohistochemically for c-Fos and alpha1 adrenoceptor by double-staining methods. Results The antinociceptive effect of N2O was attenuated by prazosin (an alpha1 adrenoceptor antagonist), yohimbine (an alpha2 adrenoceptor antagonist), and naloxone (an opioid receptor antagonist) but not by methysergide and tropisetron (serotonin receptor antagonists). N2O exposure induced c-Fos expression in the spinal cord, which was blocked by prazosin and naloxone but not by other drugs. N2O-induced c-Fos expression was colocalized with alpha1 adrenoceptor immunoreactivity in laminae III-IV. Conclusions These findings support the hypothesis that N2O activates GABAergic interneurons through alpha1 adrenoceptors to produce its antinociceptive effect.

Brain Stem Ppioidergic and GABAergic Neurons Mediate Nitrous Oxide Induced Antinociceptive Effect in Fischer Rats

2002 ◽  
Vol 96 (Sup 2) ◽  
pp. A778
Author(s):  
Yoko Ohashi ◽  
Tianzhi Guo ◽  
Ryo Orii ◽  
Mervyn Maze ◽  
Masahiko Fujinaga
Keyword(s):  
Nitrous Oxide ◽  
Brain Stem ◽  
Antinociceptive Effect ◽  
Gabaergic Neurons ◽  
Fischer Rats

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.

scholarly journals Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord

2022 ◽  
Vol 23 (2) ◽  
pp. 834
Author(s):  
Chigusa Shimizu-Okabe ◽  
Shiori Kobayashi ◽  
Jeongtae Kim ◽  
Yoshinori Kosaka ◽  
Masanobu Sunagawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Radial Glia ◽  
Ventricular Zone ◽  
Glycine Receptor ◽  
Ventral Horn ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Mouse Spinal Cord ◽  
Mature Mouse

Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine coreleasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play critical roles in regulating pain, locomotive movement, and respiratory rhythms. In this study, we first describe GABAergic and glycinergic transmission and inhibitory networks, consisting of three types of terminals in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with a specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated, and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many GABAergic neurons convert to a coreleasing state. The coreleasing neurons and terminals remain in the dorsal horn, whereas many ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.

scholarly journals Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord

2021 ◽  
Author(s):  
Chigusa Shimizu-Okabe ◽  
Shiori Kobayashi ◽  
Jeongtae Kim ◽  
Yoshinori Kosaka ◽  
Masanobu Sunagawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Radial Glia ◽  
Ventricular Zone ◽  
Glycine Receptor ◽  
Ventral Horn ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Mouse Spinal Cord ◽  
Mature Mouse

Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine co-releasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play key roles in the regulation of pain, locomotive movement, and respiratory rhythms. Herein, we first describe GABAergic and glycinergic transmission and inhibitory networks, which consist of three types of terminals, in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many of GABAergic neurons convert to co-releasing state. The co-releasing neurons and terminals remain in the dorsal horn, whereas many of co-releasing ones ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.

scholarly journals Presynaptic and Postsynaptic Effects of the Anesthetics Sevoflurane and Nitrous Oxide in the Human Spinal Cord

2007 ◽  
Vol 107 (4) ◽  
pp. 553-562 ◽  
Author(s):  
Jan H. Baars ◽  
Michael Benzke ◽  
Falk von Dincklage ◽  
Josephine Reiche ◽  
Peter Schlattmann ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Presynaptic Inhibition ◽  
Femoral Nerve ◽  
Volatile Anesthetic ◽  
H Reflex ◽  
Receptor Subtype ◽  
Gamma Aminobutyric Acid ◽  
Human Spinal Cord ◽  
Two Parameters

Background Reduced spinal excitability contributes to the suppression of movement responses to noxious stimuli during the anesthetic state. This study examines and compares presynaptic and postsynaptic effects of two anesthetics in the human spinal cord. Methods The authors tested two parameters during the administration of 0.8 vol% sevoflurane or 40 vol% nitrous oxide compared with control states before and after drug administration: (1) the size of the soleus H reflex (integrating presynaptic and postsynaptic effects) at increasing stimulus intensities (recruitment curve) and (2) the amount of presynaptic inhibition on Ia afferents of the quadriceps femoris, evaluated by the heteronymous facilitation of the soleus H reflex caused by a conditioning stimulation of the femoral nerve. The study was performed in 10 subjects for each drug. Results At the chosen concentrations, the maximum H reflex was reduced by 26.3 +/- 8.4% (mean +/- SD) during sevoflurane and by 33.5 +/- 15.6% during nitrous oxide administration. The averaged recruitment curves were similarly depressed under the influence of the two drugs. The reduction of H-reflex facilitation was significantly stronger for sevoflurane (28.8 +/- 20.0%) than for nitrous oxide administration (6.2 +/- 26.4%). Conclusions These results demonstrate in humans presynaptic effects of the volatile anesthetic sevoflurane but not of nitrous oxide. A possible explanation for this difference may be the different potency of the respective drugs in enhancing gamma-aminobutyric acid type A receptor-mediated inhibition, because presynaptic inhibition in the spinal cord involves this receptor subtype.

scholarly journals Enflurane Actions on Spinal Cords from Mice That Lack the β3Subunit of the GABAAReceptor

2001 ◽  
Vol 95 (1) ◽  
pp. 154-164 ◽  
Author(s):  
Shirley M. E. Wong ◽  
Gong Cheng ◽  
Gregg E. Homanics ◽  
Joan J. Kendig
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Dominant Role ◽  
Glycine Receptor ◽  
Excitatory Postsynaptic Potential ◽  
Evoked Responses ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Root Potential ◽  
Beta3 Subunit

Background Gamma-aminobutyric acid type A (GABA(A)) receptors are considered important in mediating anesthetic actions. Mice lacking the beta3 subunit of this receptor (beta3-/-) have a higher enflurane minimum alveolar concentration (MAC) than wild types (+/+). MAC is predominantly determined in spinal cord. Methods The authors measured three population-evoked responses in whole spinal cords, namely, the excitatory postsynaptic potential (pEPSP), the slow ventral root potential (sVRP), and the dorsal root potential. Synaptic and glutamate-evoked currents from motor neurons in spinal cord slices were also measured. Results Sensitivity of evoked responses to enflurane did not differ between +/+ and -/- cords. The GABA(A) receptor antagonist bicuculline significantly (P < 0.05) attenuated the depressant effects of enflurane on pEPSP, sVRP and glutamate-evoked currents in +/+ but not -/- cords. The glycine antagonist strychnine elevated the pEPSP to a significantly greater extent in -/- than in +/+ cords, but the interactions between strychnine and enflurane did not differ between -/- and +/+ cords. Conclusions Similar enflurane sensitivity in spinal cords from -/- and +/+ mice was coupled with a decreased role for GABA(A) receptors in mediating the actions of enflurane in the former. This finding implies that other anesthetic targets substitute for GABA(A) receptors. Increase in glycine receptor-mediated inhibition was found in -/- cords, but the glycine receptor does not appear to be a substitute anesthetic target. This mutation thus led to a quantitative change in the molecular basis for anesthetic depression of spinal neurotransmission in a fashion not predicted by the mutation itself. The results argue against an immutable dominant role for GABA(A) receptors in mediating spinal contributions to MAC.

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