Manabu Okamoto

Niigata University, Niahi-niigata, Niigata, Japan

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Publications (16)41.68 Total impact

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    ABSTRACT: Although isoflurane, a volatile anesthetic, can block the motor response to noxious stimulation (immobility and analgesia) and suppress autonomic responsiveness, how it exerts these effects at the neuronal level in the spinal cord is not fully understood. The effects of a clinically relevant concentration (1 rat minimum alveolar concentration [MAC]) of isoflurane on electrically evoked and spontaneous excitatory/inhibitory transmission and on the response to exogenous administration of the gamma-aminobutyric acid type A receptor agonist muscimol were examined in lamina II neurons of adult rat spinal cord slices using the whole cell patch clamp technique. The effect of isoflurane on the action potential-generating membrane property was also examined. Bath-applied isoflurane (1.5%, 1 rat MAC) diminished dorsal root-evoked polysynaptic but not monosynaptic excitatory postsynaptic currents. Glutamatergic miniature excitatory postsynaptic currents were also unaffected by isoflurane. In contrast, isoflurane prolonged the decay phase of evoked and miniature gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents and increased the amplitude of the muscimol-induced current. Isoflurane had little effect on action potential discharge activity. Isoflurane augments gamma-aminobutyric acid-mediated inhibitory transmission, leading to a decrease in the excitability of spinal dorsal horn neurons. This may be a possible mechanism for the antinociceptive effect of isoflurane in the spinal cord.
    Anesthesiology 03/2005; 102(2):379-86. · 5.16 Impact Factor
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    ABSTRACT: Primary afferent A-fiber stimulation normally evokes fast mono- or polysynaptic EPSCs of short duration. However, in the presence of the GABA(A) receptor antagonist bicuculline, repetitive, long lasting, polysynaptic EPSCs can be observed following the initial, fast response. A-fiber-induced ERK activation is also facilitated in the presence of bicuculline. The frequency of miniature EPSCs and the amplitude of the monosynaptic A-fiber-evoked EPSCs are not affected by bicuculline or the GABA(A) receptor agonist muscimol, suggesting that GABA(A) receptors located on somatodendritic sites of excitatory interneurons are critical for this action. Bicuculline-enhanced polysynaptic EPSCs are completely eliminated by NMDA receptor antagonists APV and ketamine, as was the augmented ERK activation. This NMDA receptor-dependent phenomenon may contribute to bicuculline-induced allodynia or hyperalgesia, as well as the hypersensitivity observed in neuropathic pain patients.
    Molecular and Cellular Neuroscience 12/2003; 24(3):818-30. · 3.84 Impact Factor
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    ABSTRACT: Spinal epidural and subarachnoid spaces were observed with the newly developed fine flexible fiberscopes in 55 patients with chronic pain. To evaluate the fiberscopes as diagnostic tools for spinal canal disease. Fine flexible fiberscopes make it possible to visualize the entire length of the spinal subarachnoid space without major complications, and they may be of value for the diagnosis of certain spinal canal diseases. The epidural and subarachnoid spaces were accessed by fine flexible fiberscopes (Purely Fine [PF] types) in the initial 45 patients and by those equipped with a tip-steering function and a working channel (Medical Science [MS] types) in the later 10 patients, respectively. The procedures were based on those of continuous epidural or subarachnoid block. Normal and abnormal subarachnoid spaces were clearly observed. When the MS types were used, the intended sites of the spinal structures could be more easily approached. In 12 patients, new diagnoses were made (chronic arachnoiditis 9, subarachnoid cyst 2, old subdural hematoma 1) that could not be found by magnetic resonance imaging or computed tomography. Additionally, chronic arachnoiditis was found in 2 patients with spinal trauma. Pathologic changes were confirmed by fiberscopic examination in 16 patients (arachnoiditis 11, spinal trauma 2, arteriovenous malformation 2, subarachnoid cyst 1). No pathologic changes could be detected in 27 patients with spinal canal stenosis, disc herniation, reflex sympathetic dystrophy, or posttraumatic pain syndrome. There were no significant differences in incidence of new diagnoses between the PF and MS types of fiberscopes. There were no major complications. There were 2 cases of light fever in the initial 10 patients and 7 cases of headache in the initial 14 patients. Only 4 cases of headache were observed in the subsequent 41 patients, in whom 20 mL of saline was injected into the epidural space. These fine flexible fiberscopes may provide new diagnostic and interventional tools for spinal canal diseases, provided skilled techniques are applied.
    Spine 10/2003; 28(17):2006-12. · 2.16 Impact Factor
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    ABSTRACT: Spinal dorsal column stimulation (DCS) modulates sensory transmission, including pain, at the dorsal horn of the cord. However, the mechanisms of DCS modulatory actions and the effects of anesthetics on these mechanisms remain to be investigated. We studied the effects of isoflurane (1.0% and 2.0%) on conditioned inhibition, the amplitude decrease of the spinal cord potentials (SCPs) after a conditioning volley (DCS), in the ketamine-anesthetized rat by recording the sharp negative (N) and slow positive (P) waves of the SCPs evoked by conditioning dorsal column (DC) and testing segmental stimulations. The N wave is believed to be the synchronized activity of the dorsal horn neurons, and the P wave, primary afferent depolarization (PAD), reflecting presynaptic inhibition. The P potentials evoked by either DC or segmental stimulation were depressed by isoflurane, whereas the N waves remained unchanged, indicating that the pharmacological characteristics of these N and P waves are similar between DC-evoked and segmentally evoked SCPs. The conditioned inhibition of segmental N and P waves by DC stimulation was almost completely suppressed by 2.0% isoflurane. The conditioned inhibition of the segmental N wave was not changed by spinal cord transection, whereas the conditioned inhibition of the segmental P wave was decreased. The results indicate that isoflurane depresses presynaptic inhibition without affecting the synchronized activity of dorsal horn neurons and, most profoundly, depresses the conditioned inhibition by DC stimulation of the dorsal horn neurons and PAD. Further, the results indicate that conditioned inhibition by DC stimulation of PAD receives a facilitatory influence from the supraspinal structures, whereas that of the synchronized activity of the dorsal horn neurons does not. IMPLICATIONS: To investigate how anesthetics affect supraspinal modulation of sensory transmission in the spinal cord, the spinal cord potential (SCP) evoked by dorsal cord stimulation (DCS) and segmentally evoked SCP conditioned by DCS were recorded in intact and spinal cord-transected rats during isoflurane anesthesia.
    Anesthesia & Analgesia 09/2003; 97(2):436-41, table of contents. · 3.30 Impact Factor
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    ABSTRACT: We report here the management of labor for a 33-year-old woman with Marfan's syndrome. She was diagnosed as Marfan's syndrome at the age of 5 and experienced corrective surgery for abdominal aortic aneurysm at 28 years of age. As there was no progression of cardiovascular lesion, she was allowed to be pregnant. She was planned to proceed with vaginal delivery, since she was in trouble of circulation during her gestational period. In order to prevent catastrophe such as aortic dissection or aortic regurgitation elicited by hypertension related with labor pain, we performed continuous epidural anesthesia to control labor pain under the invasive blood pressure monitoring. Two epidural catheters were inserted into the epidural space via the L 2-3 and the L 5-S 1 intervertebral space, and mixed solutions containing both 0.125% bupivacaine and 0.0002% fentanyl were administered continuously. After 7 hours and 47 minutes from the start of her labor, she delivered her baby vaginally with the aid of forceps technique due to attenuated abdominal muscle activity. No cardiovascular mishaps occurred during her labor and she was discharged 6 days after the delivery. Thus, continuous epidural anesthesia with intensive monitoring of circulation may be useful for vaginal delivery in a patient with Marfan's syndrome by avoiding cardiovascular complications due to labor pain.
    Masui. The Japanese journal of anesthesiology 09/2002; 51(8):916-20.
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    ABSTRACT: Although the function of somatodendritic GABAA receptors is augmented by propofol, it is not known whether presynaptic GABAA receptor function is similarly affected. In the present study, we examined the action of propofol on the second positive wave (P2 component) of segmental spinal cord evoked potentials (seg SCEPs), which is believed to reflect GABAA receptor-mediated presynaptic inhibition of primary afferent terminals and can be recorded from spinal epidural space in man. In all seven patients tested while undergoing scoliosis surgery, a clinical dose of propofol (1 mg//kg, i.v.) significantly augmented the P2 component of seg SCEPs evoked by ulner nerve stimulation. We conclude that propofol enhances GABAA receptor-mediated presynaptic inhibition at primary afferent terminals in human spinal cord.
    Neuroreport 04/2002; 13(3):357-60. · 1.40 Impact Factor
  • Neuroreport 01/2002; 13(3):357-360. · 1.40 Impact Factor
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    ABSTRACT: Functional reorganization of sensory pathways in the rat spinal dorsal horn following sciatic nerve transection was examined using spinal cord slices with an attached dorsal root. Slices were obtained from animals whose sciatic nerve had been transected 2-4 weeks previously and compared to sham-operated controls. Whole-cell recordings from substantia gelatinosa neurones in sham-operated rats, to which nociceptive information was preferentially transmitted, revealed that dorsal root stimulation sufficient to activate A afferent fibres evoked a mono- and/or polysynaptic EPSC in 111 of 131 (approximately 85%) neurones. This is in contrast to the response following A fibre stimulation, where monosynaptic EPSCs were observed in 2 of 131 (approximately 2%) neurones and polysynaptic EPSCs were observed in 18 of 131 (approximately 14%) neurones. In sciatic nerve-transected rats, however, a polysynaptic EPSC following stimulation of A afferents was elicited in 30 of 37 (81%) neurones and a monosynaptic EPSC evoked by A afferent stimulation was detected in a subset of neurones (4 of 37, approximately 11%). These observations suggest that, following sciatic nerve transection, large myelinated A afferent fibres establish synaptic contact with interneurones and transmit innocuous information to substantia gelatinosa. This functional reorganization of the sensory circuitry may constitute an underlying mechanism, at least in part, for sensory abnormalities following peripheral nerve injuries.
    The Journal of Physiology 05/2001; 532(Pt 1):241-50. · 4.38 Impact Factor
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    ABSTRACT: It has been reported previously that norepinephrine, when applied to the spinal cord dorsal horn, excites a subpopulation of dorsal horn neurons, presumably inhibitory interneurons. In the current study, the authors tested whether norepinephrine could activate inhibitory interneurons, specifically those that are "GABAergic." A transverse slice was obtained from a segment of the lumbar spinal cord isolated from adult male Sprague-Dawley rats. Whole-cell patch-clamp recordings were made from substantia gelatinosa neurons using the blind patch-clamp technique. The effects of norepinephrine on spontaneous GABAergic inhibitory postsynaptic currents were studied. In the majority of substantia gelatinosa neurons tested, norepinephrine (10-60 microM) significantly increased both the frequency and the amplitude of GABAergic inhibitory postsynaptic currents. These increases were blocked by tetrodotoxin (1 microM). The effects of norepinephrine were mimicked by the alpha1-receptor agonist phenylephrine (10-80 microM) and inhibited by the alpha1-receptor-antagonist WB-4101 (0.5 microM). Primary-afferent-evoked polysynaptic excitatory postsynaptic potentials or excitatory postsynaptic currents in wide-dynamic-range neurons of the deep dorsal horn were also attenuated by phenylephrine (40 microM). The observations suggest that GABAergic interneurons possess somatodendritic alpha1 receptors, and activation of these receptors excites inhibitory interneurons. The alpha1 actions reported herein may contribute to the analgesic action of intrathecally administered phenylephrine.
    Anesthesiology 03/2000; 92(2):485-92. · 5.16 Impact Factor
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    ABSTRACT: Although intrathecal administration of midazolam has been found to produce analgesia, how midazolam exerts this effect is not understood fully at the neuronal level in the spinal cord. The effects of midazolam on either electrically evoked or spontaneous inhibitory transmission and on a response to exogenous gamma-aminobutyric acid (GABA), a GABA(A)-receptor agonist, muscimol, or glycine were evaluated in substantia gelatinosa neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Bath-applied midazolam (1 microM) prolonged the decay phase of evoked and miniature inhibitory postsynaptic currents (IPSCs), mediated by GABA(A) receptors, without a change in amplitudes, while not affecting glycine receptor-mediated miniature inhibitory postsynaptic currents in both the decay phase and the amplitude. Either GABA- or muscimol-induced currents were enhanced in amplitude by midazolam (0.1 microM) in a manner sensitive to a benzodiazepine receptor antagonist, flumazenil (1 microM); glycine currents were, however, unaltered by midazolam. Midazolam augmented both the duration of GABA-mediated synaptic current and the amplitude of GABA-induced current by acting on the GABA(A)-benzodiazepine receptor in substantia gelatinosa neurons; this would increase the inhibitory GABAergic transmission. This may be a possible mechanism for antinociception by midazolam.
    Anesthesiology 03/2000; 92(2):507-15. · 5.16 Impact Factor
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    ABSTRACT: 1. Blind patch clamp recordings were made from substantia gelatinosa (SG) neurones in the adult rat spinal cord slice to study the mechanisms of cholinergic modulation of GABAergic inhibition. 2. In the majority of SG neurones tested, carbachol (10 microM) increased the frequency (677 % of control) of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). A portion of these events appeared to result from the generation of spikes by GABAergic interneurones, since large amplitude IPSCs were eliminated by tetrodotoxin (1 microM). 3. The effect of carbachol on spontaneous IPSCs was mimicked by neostigmine, suggesting that GABAergic interneurones are under tonic regulation by cholinergic systems. 4. The frequency of GABAergic miniature IPSCs in the presence of tetrodotoxin (1 microM) was also increased by carbachol without affecting amplitude distribution, indicating that acetylcholine facilitates quantal release of GABA through presynaptic mechanisms. 5. Neither the M1 receptor agonist McN-A-343 (10-300 microM) nor the M2 receptor agonist, arecaidine (10-100 microM), mimicked the effects of carbachol. All effects of carbachol and neostigmine were antagonized by atropine (1 muM), while pirenzepine (100 nM), methoctramine (1 microM) and hexahydrosiladifenidol hydrochloride, p-fluoro-analog (100 nM) had no effect. 6. Focal stimulation of deep dorsal horn, but not dorsolateral funiculus, evoked a similar increase in IPSC frequency to that evoked by carbachol and neostigmine. The stimulation-induced facilitation of GABAergic transmission lasted for 2-3 min post stimulation, and the effect was antagonized by atropine (100 nM). 7. Our observations suggest that GABAergic interneurones possess muscarinic receptors on both axon terminals and somatodendritic sites, that the activation of these receptors increases the excitability of inhibitory interneurones and enhances GABA release in SG and that the GABAergic inhibitory system is further controlled by cholinergic neurones located in the deep dorsal horn. Those effects may be responsible for the antinociceptive action produced by the intrathecal administration of muscarinic agonists and acetylcholinesterase inhibitors.
    The Journal of Physiology 05/1998; 508 ( Pt 1):83-93. · 4.38 Impact Factor
  • Neuroscience Research - NEUROSCI RES. 01/1998; 31.
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    ABSTRACT: Whole-cell patch-clamp recordings were made from neurons in the substantia gelatinosa of adult rat spinal cord slices with attached dorsal root to study a slow synaptic current evoked by focal or dorsal root stimulation. Repetitive focal stimulation with a monopolar electrode positioned within substantia gelatinosa elicited a slow excitatory postsynaptic current preceded by a fast excitatory postsynaptic current in 73 of 83 neurons. A similar slow excitatory postsynaptic current was also elicited by stimulation of A delta afferent fibres. The amplitude of slow excitatory postsynaptic currents was unchanged when the recording electrode contained guanosine-5'-O-(2-thiodiphosphate). The slow excitatory postsynaptic current and current evoked by aspartate revealed similar reversal potentials and showed a marked outward rectification at holding potentials more negative than -30 mV, while the glutamate-induced current exhibited a relatively linear voltage relationship. In addition, the slow excitatory postsynaptic currents were reversibly occluded during the aspartate-induced current but were not occluded during the glutamate-induced current. The slow excitatory postsynaptic currents evoked by focal stimulation were depressed but not abolished by 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) or by 6-cyano-7-nitroquinoxaline-2,3-dione together with DL-2-amino-5-phosphonopentanoic acid (100 microM). Similarly, the aspartate- and glutamate-induced currents were also resistant to these antagonists. These observations suggest that a transmitter released from interneurons or descending fibres which are activated in part by A delta afferents, mediates a slow excitatory postsynaptic currents in substantia gelatinosa neurons and that an excitatory amino acid is implicated in the generation of the slow excitatory postsynaptic current, although the receptor appears to differ from the known ligand-gated channels. C afferents are unlikely to contribute to the slow excitatory postsynaptic current. This slow synaptic response may participate in the pain pathway and play an important role in the processing of nociceptive information in the spinal dorsal horn.
    Neuroscience 03/1997; 76(3):673-88. · 3.12 Impact Factor
  • Neuroscience Research - NEUROSCI RES. 01/1996; 25.
  • Neuroscience Research - NEUROSCI RES. 01/1996; 25.
  • Neuroscience Research 12/1995; 25:162-162. · 2.20 Impact Factor