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Megumu Yoshimura - One of the best experts on this subject based on the ideXlab platform.
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Effects of naftopidil on inhibitory transmission in Substantia gelatinosa neurons of the rat spinal dorsal horn in vitro.
Journal of the neurological sciences, 2017Co-Authors: Daisuke Uta, Du-jie Xie, Tsuyoshi Hattori, Ken-ichi Kasahara, Megumu YoshimuraAbstract:Abstract Objective Naftopidil is used clinically for the treatment of voiding disorders in benign prostatic hyperplasia. Previous in vivo experiments in which naftopidil was applied intrathecally abolished rhythmic bladder contraction, suggesting that naftopidil might inhibit a voiding reflex through interaction with spinal dorsal horn neurons. Here we aimed to clarify the mechanism of action of naftopidil on dorsal horn neurons. Methods Whole-cell patch-clamp recordings were performed using Substantia gelatinosa neurons of adult rat spinal cord slices. Miniature or evoked inhibitor and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were analyzed. Results Bath-applied naftopidil increased the frequency but not the amplitude of miniature IPSCs (mIPSCs) in 38% of neurons tested; in contrast, the effect of naftopidil on miniature EPSCs (mEPSCs) were mild and observed in only 2 out of 19 neurons. Naftopidil enhanced the amplitude of both GABAergic and glycinergic evoked-IPSCs (eIPSCs) that were elicited by focal stimuli in the presence of either the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV). Conclusions Although naftopidil was developed as an alpha-1 adrenoceptor antagonist, our previous spinal cord slice experiments showed that the activation of an alpha-1 adrenoceptor in Substantia gelatinosa increases the frequency of mIPSCs. This result suggested that, under our conditions, naftopidil may interact with a receptor(s) other than an alpha-1 adrenoceptor in the spinal dorsal horn. The present results suggested that naftopidil enhances the release of GABA and glycine by activating inhibitory interneuron terminals in the spinal dorsal horn via a receptor other than an alpha-1 adrenoceptor, thereby modulating sensory transmission in the Substantia gelatinosa.
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Enhancement of GABAergic tonic currents by midazolam and noradrenaline in rat Substantia gelatinosa neurons in vitro.
Anesthesiology, 2010Co-Authors: Aiko Maeda, Toshihiko Katafuchi, Yugo Oba, Hiroaki Shiokawa, Megumu YoshimuraAbstract:Background Substantia gelatinosa of the spinal dorsal horn is crucial for transmission and modification of noxious stimuli. Previous studies have demonstrated that intrathecal midazolam, a benzodiazepine agonist, enhanced perioperative analgesia. Not only synaptic but also extrasynaptic inhibitory currents contribute to modification of noxious stimuli. Thus, the effects of midazolam on extrasynaptic gamma-aminobutyric acid (GABA) type A receptors in Substantia gelatinosa neurons and interaction with noradrenaline, a transmitter of the descending inhibitory systems, were investigated. Methods Using whole cell patch-clamp technique in the adult rat spinal cord slices, extrasynaptic GABAergic currents were recorded in Substantia gelatinosa neurons in the presence of gabazine (1 microm), which blocked synaptic GABAergic currents, and then midazolam (5 microm) and noradrenaline (20 microm) were applied. Results Bath application of midazolam induced tonic outward currents in the presence of gabazine. Although the decay time of synaptic current was prolonged, neither frequency nor amplitude was affected by midazolam. In contrast, the application of noradrenaline markedly increased both frequency and amplitude of synaptic currents with a slight enhancement of tonic currents. Coapplication of noradrenaline and midazolam markedly increased tonic currents, and the increase was much greater than the sum of currents induced by noradrenaline and midazolam. Conclusions Midazolam had much larger effects on extrasynaptic GABA type A receptors than the synaptic receptors, suggesting a role of the enhancement of GABAergic extrasynaptic currents in the midazolam-induced analgesia. Because noradrenaline is shown to increase extrasynaptic GABA concentration, simultaneous administration of noradrenaline and midazolam may enhance the increased GABA action by midazolam, thereby resulting in an increase in tonic extrasynaptic currents.
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Changes in properties of Substantia gelatinosa neurons after surgical incision in the rat: in vivo patch-clamp analysis.
Anesthesiology, 2006Co-Authors: Mikito Kawamata, Hidemasa Furue, Megumu Yoshimura, Yuji Kozuka, Eichi Narimatsu, Akiyoshi NamikiAbstract:Background: Noxious information through AS and C afferent fibers is transmitted to Substantia gelatinosa, a process that plays an important role in plastic changes of nociceptive processing in pathophysiological conditions. In this study, changes in properties of Substantia gelatinosa neurons and their sensitivity to systemic administration of lidocaine after surgical incision were investigated using the in vivo patch-clamp technique. Methods: Under urethane anesthesia, in the current clamp mode, spontaneous activities and responses of Substantia gelatinosa neurons to nonnoxious air-puff stimuli and noxious pinch stimuli were recorded before and after 1-cm-long incisions had been made in hairy skin of the hindquarters of rats. Systemic administration of lidocaine (2 mg/kg) was applied at 30 min after the incision. Results: Stable recordings for 30 min or more after the incision were obtained from 18 Substantia gelatinosa neurons that were classified as multireceptive (n = 8), nociceptive (n = 5), and subthreshold (n = 5) neurons. Action potential firing disappeared immediately after completion of the wound closure in most multireceptive and nociceptive neurons, and sustained spontaneous action potential firing was observed in 23% of these Substantia gelatinosa neurons. Responsiveness of these Substantia gelatinosa neurons, but not that of subthreshold neurons, increased after the incision. Systemic administration of lidocaine suppressed spontaneous firings of action potentials of the Substantia gelatinosa neurons and reversed the increased responsiveness of the neurons. Conclusions: The results suggest that (1) changes in properties of Substantia gelatinosa neurons after incision vary depending on the classification of Substantia gelatinosa neurons and (2) systemic administration of lidocaine can reverse increased responsiveness of Substantia gelatinosa neurons after incision injury.
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Action of neuropeptide Y on nociceptive transmission in Substantia gelatinosa of the adult rat spinal dorsal horn.
Neuroscience, 2005Co-Authors: A. Miyakawa, Hidemasa Furue, Toshihiko Katafuchi, Nan Jiang, Toshiharu Yasaka, Go Kato, Megumu YoshimuraAbstract:Abstract Effects of neuropeptide Y (NPY) on Substantia gelatinosa neurons were investigated in adult rat spinal cord slices using blind whole-cell patch-clamp technique. Bath application of NPY (1μM) induced a membrane hyperpolarization, resulting in a suppression of the dorsal root stimulation-induced action potentials in 24% of the Substantia gelatinosa neurons tested. In voltage clamp mode, NPY produced an outward current dose-dependently in about one third of Substantia gelatinosa neurons at the holding potential of −60 mV, which was not affected by tetrodotoxin (1μM). The NPY-induced current was suppressed by perfusion with a Ba2+-containing external solution and a Cs2SO4 or tetraethylammonium-containing pipette solution. In addition, The NPY-induced outward currents reversed its polarity near the equilibrium potential of K+ ions (−93 mV). The response to NPY recorded with guanosine-5′-O-(2-thiodiphosphate)-β-S (GDP-β-S) containing pipette solution was abolished 30 min after patch formation, suggesting that the response was mediated by the G-protein-coupled receptors. Application of an NPY-Y1 selective agonist, [Leu31, Pro-34]-NPY (1μM), for 30 s also induced an outward current with a similar time course and amplitude to that induced by NPY. On the other hand, the NPY response was blocked by a simultaneous application of NPY-Y1 selective antagonist, BIBP 3226 (1μM). No significant changes were found in amplitude and frequency of miniature excitatory postsynaptic currents and dorsal root evoked excitatory postsynaptic currents by NPY. In addition, NPY did not affect both of the miniature inhibitory postsynaptic currents and evoked inhibitory postsynaptic currents, mediated by either the GABA or glycine receptor. These findings, taken together, suggest that NPY produces an outward current in Substantia gelatinosa neurons through G-protein coupled, and NPY-Y1 receptor-mediated activation of K+ channels without affecting presynaptic components. The inhibition of the synaptic transmission from the primary fibers to the Substantia gelatinosa neurons is considered to contribute to the antinociceptive effects of NPY.
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α2 adrenoceptor mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat Substantia gelatinosa neurons
Anesthesiology, 2003Co-Authors: Yasuhiko Kawasaki, Hidemasa Furue, Eiichi Kumamoto, Megumu YoshimuraAbstract:Background: Although intrathecal administration of norepinephrine is known to produce analgesia, cellular mechanisms for this action have not yet been fully understood. Methods: The actions of norepinephrine (50 microm) on glutamatergic transmission were examined by using the whole cell patch clamp technique in Substantia gelatinosa neurons of an adult rat spinal cord slice with an attached dorsal root. Results: Norepinephrine inhibited the amplitude of monosynaptically evoked A delta-fiber and C-fiber excitatory postsynaptic currents in a reversible manner. When compared in magnitude between the A delta-fiber and C-fiber excitatory postsynaptic currents, the former inhibition (50 +/- 4%, n = 20) was significantly larger than the latter one (28 +/- 4%, n = 8). Both actions of norepinephrine were mimicked by an alpha2 adrenoceptor agonist, clonidine (10 microm), and an alpha 2A agonist, oxymetazoline (10 microm), but not by an alpha1 agonist, phenylephrine (10 microm), and a beta agonist, isoproterenol (40 microm). The inhibitory actions were antagonized by an alpha 2 antagonist, yohimbine (1 microm), all of the results of which indicate an involvement of alpha 2 adrenoceptors. Norepinephrine did not affect the amplitude of miniature excitatory postsynaptic current and of a response of Substantia gelatinosa neurons to AMPA, indicating that its action on evoked excitatory postsynaptic currents is presynaptic in origin. Conclusions: Norepinephrine inhibits A delta-fiber- and C-fiber-mediated sensory transmission to Substantia gelatinosa neurons through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in A delta-fiber than C-fiber transmission. This could contribute to at least a part of inhibitory modulation of pain sensation in the Substantia gelatinosa by intrathecally administered norepinephrine.
Eiichi Kumamoto - One of the best experts on this subject based on the ideXlab platform.
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Zingerone enhances glutamatergic spontaneous excitatory transmission by activating TRPA1 but not TRPV1 channels in the adult rat Substantia gelatinosa
Journal of neurophysiology, 2013Co-Authors: H.-y. Yue, Tsugumi Fujita, Changyu Jiang, Eiichi KumamotoAbstract:Transient receptor potential (TRP) channels are thought to play a role in regulating nociceptive transmission to spinal Substantia gelatinosa (SG) neurons. It remains to be unveiled whether the TRP...
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Acetylcholine and norepinephrine mediate GABAergic but not glycinergic transmission enhancement by melittin in adult rat Substantia gelatinosa neurons
Journal of neurophysiology, 2011Co-Authors: Tao Liu, Tsugumi Fujita, Eiichi KumamotoAbstract:GABAergic and glycinergic inhibitory synaptic transmissions in Substantia gelatinosa (SG; lamina II of Rexed) neurons of the spinal dorsal horn play an important role in regulating nociceptive tran...
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Phospholipase A2 Activation Enhances Inhibitory Synaptic Transmission in Rat Substantia gelatinosa Neurons
Journal of neurophysiology, 2008Co-Authors: Tao Liu, Tsugumi Fujita, Terumasa Nakatsuka, Eiichi KumamotoAbstract:Phospholipase A2 (PLA2) activation enhances glutamatergic excitatory synaptic transmission in Substantia gelatinosa (SG) neurons, which play a pivotal role in regulating nociceptive transmission in...
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Inhibition by endomorphin-1 and endomorphin-2 of excitatory transmission in adult rat Substantia gelatinosa neurons
Neuroscience, 2006Co-Authors: Tsugumi Fujita, Eiichi KumamotoAbstract:Intrathecally-administered endomorphin-1 and endomorphin-2 produce antinociceptive effects which are different from each other. In order to elucidate a cellular basis for this result, we examined the effects of endomorphin-1 and endomorphin-2 on holding currents and spontaneous glutamatergic excitatory transmission in Substantia gelatinosa neurons of adult rat spinal cord slices by use of the whole-cell patch-clamp technique. In about half of the neurons examined, endomorphin-1 and endomorphin-2 produced an outward current having a similar amplitude (25-27 pA at 1 microM) at -70 mV with almost the same value of effective concentration producing half-maximal response (0.19-0.21 microM). Both of them reversed at a potential close to the equilibrium potential for K+, and had the slope conductance that was larger at negative (-120 to -140 mV) than positive potentials (-60 to -90 mV). The endomorphin-1 and endomorphin-2 currents were reduced in amplitude by K+-channel inhibitors, Ba2+ (100 microM) and 4-aminopyridine (1 mM), and also by mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (1 microM) to a similar extent. The endomorphin-2 but not endomorphin-1 current amplitude was increased by dipeptidyl peptidase IV inhibitor diprotin A (30 microM). One micromolar endomorphin-1 and endomorphin-2 reduced the frequency of spontaneous excitatory postsynaptic current with a similar time course and extent without altering its amplitude; these actions were not in the presence of D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (1 microM). We conclude that endomorphin-1 and endomorphin-2 hyperpolarize membranes by opening inwardly-rectifying K+ channels and attenuate the spontaneous release of L-glutamate from nerve terminals in the Substantia gelatinosa, both of which are mediated by mu-opioid receptors, in a manner quantitatively similar to each other. The difference in antinociceptive effects between endomorphin-1 and endomorphin-2 could not be attributed to a distinction in their effects on excitatory transmission in Substantia gelatinosa neurons, and may be explained by a difference in their enzymatic degradation.
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Phospholipase A2 activation by melittin enhances spontaneous glutamatergic excitatory transmission in rat Substantia gelatinosa neurons.
Neuroscience, 2005Co-Authors: H.-y. Yue, Tsugumi Fujita, Eiichi KumamotoAbstract:Abstract In order to know a role of phospholipase A 2 in modulating nociceptive transmission, the effect of a secreted phospholipase A 2 activator melittin on spontaneous glutamatergic excitatory transmission was investigated in Substantia gelatinosa neurons of an adult rat spinal cord slice by using the whole-cell patch-clamp technique. Bath-applied melittin at concentrations higher than 0.5μM increased both the amplitude and the frequency of spontaneous excitatory postsynaptic current in a manner independent of tetrodotoxin; the latter effect of which was examined in detail. In 80% of the neurons examined ( n =64), melittin superfused for 3 min gradually increased spontaneous excitatory postsynaptic current frequency (by 65±6% at 1μM; n =51) in a dose-dependent manner (effective concentration for half-maximal effect=1.1μM). This effect subsided within 3 min after washout. The spontaneous excitatory postsynaptic current frequency increase produced by melittin was reduced by the phospholipase A 2 inhibitor 4-bromophenacryl bromide (10μM) while being unaffected by the cyclooxygenase inhibitor indomethacin (100μM) and the lipoxygenase inhibitor nordihydroguaiaretic acid (100μM). A similar increase in spontaneous excitatory postsynaptic current frequency was produced by exogenous arachidonic acid (50μM); this effect was also unaffected by the cyclooxygenase or lipoxygenase inhibitor. Melittin failed to increase spontaneous excitatory postsynaptic current frequency in a nominally Ca 2+ -free or La 3+ -containing Krebs solution. We conclude that melittin increases the spontaneous release of l -glutamate to Substantia gelatinosa neurons by activating secreted phospholipase A 2 and increasing Ca 2+ influx through voltage-gated Ca 2+ channels in nerve terminals, probably with an involvement of arachidonic acid but not its metabolites produced by cyclooxygenase and lipoxygenase. Considering that the Substantia gelatinosa plays an important role in regulating nociceptive transmission, it is suggested that this transmission may be positively modulated by secreted phospholipase A 2 activation in the Substantia gelatinosa.
Hidemasa Furue - One of the best experts on this subject based on the ideXlab platform.
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changes in synaptic transmission of Substantia gelatinosa neurons after spinal cord hemisection revealed by analysis using in vivo patch clamp recording
Molecular Pain, 2016Co-Authors: Yuji Kozuka, Hidemasa Furue, Mikito Kawamata, Takashi Ishida, Satoshi Tanaka, Akiyoshi Namiki, Michiaki YamakageAbstract:BackgroundAfter spinal cord injury, central neuropathic pain develops in the majority of spinal cord injury patients. Spinal hemisection in rats, which has been developed as an animal model of spinal cord injury in humans, results in hyperexcitation of spinal dorsal horn neurons soon after the hemisection and thereafter. The hyperexcitation is likely caused by permanent elimination of the descending pain systems. We examined the change in synaptic transmission of Substantia gelatinosa neurons following acute spinal hemisection by using an in vivo whole-cell patch-clamp technique.ResultsAn increased spontaneous action potential firings of Substantia gelatinosa neurons was detected in hemisected rats compared with that in control animals. The frequencies and amplitudes of spontaneous excitatory postsynaptic currents and of evoked excitatory postsynaptic currentss in response to non-noxious and noxious stimuli were not different between hemisected and control animals. On the contrary, the amplitude and frequ...
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Changes in properties of Substantia gelatinosa neurons after surgical incision in the rat: in vivo patch-clamp analysis.
Anesthesiology, 2006Co-Authors: Mikito Kawamata, Hidemasa Furue, Megumu Yoshimura, Yuji Kozuka, Eichi Narimatsu, Akiyoshi NamikiAbstract:Background: Noxious information through AS and C afferent fibers is transmitted to Substantia gelatinosa, a process that plays an important role in plastic changes of nociceptive processing in pathophysiological conditions. In this study, changes in properties of Substantia gelatinosa neurons and their sensitivity to systemic administration of lidocaine after surgical incision were investigated using the in vivo patch-clamp technique. Methods: Under urethane anesthesia, in the current clamp mode, spontaneous activities and responses of Substantia gelatinosa neurons to nonnoxious air-puff stimuli and noxious pinch stimuli were recorded before and after 1-cm-long incisions had been made in hairy skin of the hindquarters of rats. Systemic administration of lidocaine (2 mg/kg) was applied at 30 min after the incision. Results: Stable recordings for 30 min or more after the incision were obtained from 18 Substantia gelatinosa neurons that were classified as multireceptive (n = 8), nociceptive (n = 5), and subthreshold (n = 5) neurons. Action potential firing disappeared immediately after completion of the wound closure in most multireceptive and nociceptive neurons, and sustained spontaneous action potential firing was observed in 23% of these Substantia gelatinosa neurons. Responsiveness of these Substantia gelatinosa neurons, but not that of subthreshold neurons, increased after the incision. Systemic administration of lidocaine suppressed spontaneous firings of action potentials of the Substantia gelatinosa neurons and reversed the increased responsiveness of the neurons. Conclusions: The results suggest that (1) changes in properties of Substantia gelatinosa neurons after incision vary depending on the classification of Substantia gelatinosa neurons and (2) systemic administration of lidocaine can reverse increased responsiveness of Substantia gelatinosa neurons after incision injury.
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Action of neuropeptide Y on nociceptive transmission in Substantia gelatinosa of the adult rat spinal dorsal horn.
Neuroscience, 2005Co-Authors: A. Miyakawa, Hidemasa Furue, Toshihiko Katafuchi, Nan Jiang, Toshiharu Yasaka, Go Kato, Megumu YoshimuraAbstract:Abstract Effects of neuropeptide Y (NPY) on Substantia gelatinosa neurons were investigated in adult rat spinal cord slices using blind whole-cell patch-clamp technique. Bath application of NPY (1μM) induced a membrane hyperpolarization, resulting in a suppression of the dorsal root stimulation-induced action potentials in 24% of the Substantia gelatinosa neurons tested. In voltage clamp mode, NPY produced an outward current dose-dependently in about one third of Substantia gelatinosa neurons at the holding potential of −60 mV, which was not affected by tetrodotoxin (1μM). The NPY-induced current was suppressed by perfusion with a Ba2+-containing external solution and a Cs2SO4 or tetraethylammonium-containing pipette solution. In addition, The NPY-induced outward currents reversed its polarity near the equilibrium potential of K+ ions (−93 mV). The response to NPY recorded with guanosine-5′-O-(2-thiodiphosphate)-β-S (GDP-β-S) containing pipette solution was abolished 30 min after patch formation, suggesting that the response was mediated by the G-protein-coupled receptors. Application of an NPY-Y1 selective agonist, [Leu31, Pro-34]-NPY (1μM), for 30 s also induced an outward current with a similar time course and amplitude to that induced by NPY. On the other hand, the NPY response was blocked by a simultaneous application of NPY-Y1 selective antagonist, BIBP 3226 (1μM). No significant changes were found in amplitude and frequency of miniature excitatory postsynaptic currents and dorsal root evoked excitatory postsynaptic currents by NPY. In addition, NPY did not affect both of the miniature inhibitory postsynaptic currents and evoked inhibitory postsynaptic currents, mediated by either the GABA or glycine receptor. These findings, taken together, suggest that NPY produces an outward current in Substantia gelatinosa neurons through G-protein coupled, and NPY-Y1 receptor-mediated activation of K+ channels without affecting presynaptic components. The inhibition of the synaptic transmission from the primary fibers to the Substantia gelatinosa neurons is considered to contribute to the antinociceptive effects of NPY.
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α2 adrenoceptor mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat Substantia gelatinosa neurons
Anesthesiology, 2003Co-Authors: Yasuhiko Kawasaki, Hidemasa Furue, Eiichi Kumamoto, Megumu YoshimuraAbstract:Background: Although intrathecal administration of norepinephrine is known to produce analgesia, cellular mechanisms for this action have not yet been fully understood. Methods: The actions of norepinephrine (50 microm) on glutamatergic transmission were examined by using the whole cell patch clamp technique in Substantia gelatinosa neurons of an adult rat spinal cord slice with an attached dorsal root. Results: Norepinephrine inhibited the amplitude of monosynaptically evoked A delta-fiber and C-fiber excitatory postsynaptic currents in a reversible manner. When compared in magnitude between the A delta-fiber and C-fiber excitatory postsynaptic currents, the former inhibition (50 +/- 4%, n = 20) was significantly larger than the latter one (28 +/- 4%, n = 8). Both actions of norepinephrine were mimicked by an alpha2 adrenoceptor agonist, clonidine (10 microm), and an alpha 2A agonist, oxymetazoline (10 microm), but not by an alpha1 agonist, phenylephrine (10 microm), and a beta agonist, isoproterenol (40 microm). The inhibitory actions were antagonized by an alpha 2 antagonist, yohimbine (1 microm), all of the results of which indicate an involvement of alpha 2 adrenoceptors. Norepinephrine did not affect the amplitude of miniature excitatory postsynaptic current and of a response of Substantia gelatinosa neurons to AMPA, indicating that its action on evoked excitatory postsynaptic currents is presynaptic in origin. Conclusions: Norepinephrine inhibits A delta-fiber- and C-fiber-mediated sensory transmission to Substantia gelatinosa neurons through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based on the current, published behavioral and anatomical data) existing in primary afferent terminals; this action of norepinephrine is more effective in A delta-fiber than C-fiber transmission. This could contribute to at least a part of inhibitory modulation of pain sensation in the Substantia gelatinosa by intrathecally administered norepinephrine.
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GABA-mediated inhibition of glutamate release during ischemia in Substantia gelatinosa of the adult rat.
Journal of neurophysiology, 2003Co-Authors: Noriaki Matsumoto, Hidemasa Furue, Eiichi Kumamoto, Megumu YoshimuraAbstract:An ischemia-induced change in glutamatergic transmission was investigated in Substantia gelatinosa (SG) neurons of adult rat spinal cord slices by use of the whole cell patch-clamp technique; the i...
Mikito Kawamata - One of the best experts on this subject based on the ideXlab platform.
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changes in synaptic transmission of Substantia gelatinosa neurons after spinal cord hemisection revealed by analysis using in vivo patch clamp recording
Molecular Pain, 2016Co-Authors: Yuji Kozuka, Hidemasa Furue, Mikito Kawamata, Takashi Ishida, Satoshi Tanaka, Akiyoshi Namiki, Michiaki YamakageAbstract:BackgroundAfter spinal cord injury, central neuropathic pain develops in the majority of spinal cord injury patients. Spinal hemisection in rats, which has been developed as an animal model of spinal cord injury in humans, results in hyperexcitation of spinal dorsal horn neurons soon after the hemisection and thereafter. The hyperexcitation is likely caused by permanent elimination of the descending pain systems. We examined the change in synaptic transmission of Substantia gelatinosa neurons following acute spinal hemisection by using an in vivo whole-cell patch-clamp technique.ResultsAn increased spontaneous action potential firings of Substantia gelatinosa neurons was detected in hemisected rats compared with that in control animals. The frequencies and amplitudes of spontaneous excitatory postsynaptic currents and of evoked excitatory postsynaptic currentss in response to non-noxious and noxious stimuli were not different between hemisected and control animals. On the contrary, the amplitude and frequ...
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Changes in properties of Substantia gelatinosa neurons after surgical incision in the rat: in vivo patch-clamp analysis.
Anesthesiology, 2006Co-Authors: Mikito Kawamata, Hidemasa Furue, Megumu Yoshimura, Yuji Kozuka, Eichi Narimatsu, Akiyoshi NamikiAbstract:Background: Noxious information through AS and C afferent fibers is transmitted to Substantia gelatinosa, a process that plays an important role in plastic changes of nociceptive processing in pathophysiological conditions. In this study, changes in properties of Substantia gelatinosa neurons and their sensitivity to systemic administration of lidocaine after surgical incision were investigated using the in vivo patch-clamp technique. Methods: Under urethane anesthesia, in the current clamp mode, spontaneous activities and responses of Substantia gelatinosa neurons to nonnoxious air-puff stimuli and noxious pinch stimuli were recorded before and after 1-cm-long incisions had been made in hairy skin of the hindquarters of rats. Systemic administration of lidocaine (2 mg/kg) was applied at 30 min after the incision. Results: Stable recordings for 30 min or more after the incision were obtained from 18 Substantia gelatinosa neurons that were classified as multireceptive (n = 8), nociceptive (n = 5), and subthreshold (n = 5) neurons. Action potential firing disappeared immediately after completion of the wound closure in most multireceptive and nociceptive neurons, and sustained spontaneous action potential firing was observed in 23% of these Substantia gelatinosa neurons. Responsiveness of these Substantia gelatinosa neurons, but not that of subthreshold neurons, increased after the incision. Systemic administration of lidocaine suppressed spontaneous firings of action potentials of the Substantia gelatinosa neurons and reversed the increased responsiveness of the neurons. Conclusions: The results suggest that (1) changes in properties of Substantia gelatinosa neurons after incision vary depending on the classification of Substantia gelatinosa neurons and (2) systemic administration of lidocaine can reverse increased responsiveness of Substantia gelatinosa neurons after incision injury.
Hung-li Wang - One of the best experts on this subject based on the ideXlab platform.
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Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in Substantia gelatinosa neurons
Journal of Neuroinflammation, 2014Co-Authors: Chung-yu Huang, Ying-ling Chen, Hung-li WangAbstract:Background Several lines of evidence suggest that CCL2 could initiate the hyperalgesia of neuropathic pain by causing central sensitization of spinal dorsal horn neurons and facilitating nociceptive transmission in the spinal dorsal horn. The cellular and molecular mechanisms by which CCL2 enhances spinal pain transmission and causes hyperalgesia remain unknown. The Substantia gelatinosa (lamina II) of the spinal dorsal horn plays a critical role in nociceptive transmission. An activated spinal microglia, which is believed to release pro-inflammatory cytokines including TNF-α, plays an important role in the development of neuropathic pain, and CCL2 is a key mediator for spinal microglia activation. In the present study, we tested the hypothesis that spinal CCL2 causes the central sensitization of Substantia gelatinosa neurons and enhances spinal nociceptive transmission by activating the spinal microglia and augmenting glutamatergic transmission in lamina II neurons. Methods CCL2 was intrathecally administered to 2-month-old male rats. An intrathecal injection of CCL2 induced heat hyperalgesia, which was assessed using the hot plate test. Whole-cell voltage-clamp recordings Substantia gelatinosa neurons in spinal cord slices were performed to record glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs). Results The hot plate test showed that 1 day after the intrathecal injection of CCL2 (1 μg), the latency of hind-paw withdrawal caused by a heat stimulus was significantly reduced in rats. One day after the intrathecal administration of CCL2, the amplitude of the evoked glutamatergic EPSCs and the frequency of spontaneous glutamatergic miniature EPSCs (mEPSCs) were significantly increased in outer lamina II neurons. Intrathecal co-injection of minocycline, a specific inhibitor of microglial activation, and CCL2 blocked the CCL2-induced reduction in the latency of hind-paw withdrawal and thermal hyperalgesia. Following intrathecal co-administration of CCL2 and minocycline, CCL2 failed to increase the frequency of glutamatergic mEPSCs and failed to promote glutamine release in lamina II neurons. Intrathecal co-injection of WP9QY, a selective TNF-α antagonist, and CCL2 completely inhibited CCL2-induced heat hyperalgesia and inhibited the increase in the frequency of glutamatergic mEPSCs in Substantia gelatinosa neurons. Conclusion In summary, our results suggest that an intrathecal injection of CCL2 causes thermal hyperalgesia by augmenting the excitatory glutamatergic transmission in Substantia gelatinosa neurons through a presynaptic mechanism and facilitating nociceptive transmission in the spinal dorsal horn. Further studies show that intrathecal co-administration of minocycline, a specific inhibitor of microglial activation, or WP9QY, a selective TNF-α antagonist, completely inhibited CCL2 potentiation of glutamatergic transmission in Substantia gelatinosa neurons and CCL2-induced heat hyperalgesia. The results of the present study suggest that peripheral nerve injury-induced upregulation of the spinal CCL2 level causes the central sensitization of Substantia gelatinosa neurons by activating spinal microglia and that TNF-α mediates CCL2-induced thermal hyperalgesia and augmentation of glutamatergic transmission in lamina II neurons.
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Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in Substantia gelatinosa neurons
Journal of neuroinflammation, 2014Co-Authors: Chung-yu Huang, Ying-ling Chen, Hung-li WangAbstract:Background Several lines of evidence suggest that CCL2 could initiate the hyperalgesia of neuropathic pain by causing central sensitization of spinal dorsal horn neurons and facilitating nociceptive transmission in the spinal dorsal horn. The cellular and molecular mechanisms by which CCL2 enhances spinal pain transmission and causes hyperalgesia remain unknown. The Substantia gelatinosa (lamina II) of the spinal dorsal horn plays a critical role in nociceptive transmission. An activated spinal microglia, which is believed to release pro-inflammatory cytokines including TNF-α, plays an important role in the development of neuropathic pain, and CCL2 is a key mediator for spinal microglia activation. In the present study, we tested the hypothesis that spinal CCL2 causes the central sensitization of Substantia gelatinosa neurons and enhances spinal nociceptive transmission by activating the spinal microglia and augmenting glutamatergic transmission in lamina II neurons.
