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Megumu Yoshimura

Publications and source records attributed to Megumu Yoshimura.

At least 19 recordsLinked to original sources
PubMed2006

Recent advances in basic neurosciences and brain disease: from synapses to behavior.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29-31, 2007).

Behavior↗
PubMed2006

Tonic inhibitory role of alpha4beta2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice.

In the spinal dorsal horn, activation of the nicotinic acetylcholine receptors (nAChR) by exogenously applied agonists is known to enhance inhibitory synaptic transmission, and to produce analgesia. However, it is still unknown whether endogenously released acetylcholine exerts a tonic inhibition on nociceptive transmission through the nAChRs in the spinal dorsal horn. Here, we report the presence of such a tonic inhibitory mechanism in the spinal dorsal horn in mice. In behavioral experiments, intrathecal (i.t.) injection of non-selective nAChR antagonist mecamylamine and alpha4beta2 subtype-selective antagonist dihydro-beta-erythroidine (DHbetaE) dose-dependently induced thermal and mechanical hyperalgesia in mice while the alpha7-selective antagonist methyllycaconitine (MLA) had no effect. Similarly, antisense knock-down of alpha4 subunit of nAChR, but not alpha7 subunit, in spinal cord induced thermal and mechanical hyperalgesia. In whole-cell patch-clamp experiments in spinal cord slice preparation from adult mice, the frequency of miniature inhibitory postsynaptic currents (mIPSCs) observed in substantia gelatinosa (SG) neurons was decreased by mecamylamine and DHbetaE, but not by MLA. The amplitudes of the mIPSCs were not affected. The nicotinic antagonists decreased the frequency of both GABAergic and glycinergic IPSCs. On the other hand, the nicotinic antagonists had no effect on the excitatory postsynaptic currents (EPSCs). Finally, acetylcholine-esterase inhibitor neostigmine-induced facilitation of IPSC frequencies in SG neurons was inhibited by mecamylamine and DHbetaE. Altogether these findings suggest that nicotinic cholinergic system in the spinal dorsal horn can tonically inhibit nociceptive transmission through presynaptic facilitation of inhibitory neurotransmission in SG via the alpha4beta2 subtype of nAChR.

Adaptation, Physiological↗
PubMed2006

Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord.

The sensation of pain plays a critical role as an alert and as a protection system against tissue damage from mechanical, chemical, and thermal stimuli. Despite the protective role of pain, the severity of pain sensation is markedly attenuated by the endogenous pain inhibitory systems that predominantly originate at the brain stem. Both behavioral and in vivo extracellular recording studies have sought the loci producing analgesia and clarification of the anti-nociceptive actions. Among those loci, the main descending systems to the spinal dorsal horn are noradrenergic and serotonergic. Although, in vivo studies have provided basic knowledge of these systems, the precise synaptic mechanisms underlying the analgesic actions have not yet been elucidated until recently. The newly developed in vitro slice and in vivo patch-clamp recordings have disclosed the synaptic mechanisms of the noradrenergic and serotonergic effects at the level of spinal dorsal horn. This paper reviews the anti-nociceptive action of these systems, while particularly focusing on the electrophysiological aspects of the systems at the single neuron level in the spinal dorsal horn as well as their origins and responsible receptor subtypes.

Animals↗
PubMed2006

Direct excitation of deep dorsal horn neurones in the rat spinal cord by the activation of postsynaptic P2X receptors.

ATP mediates somatosensory transmission in the spinal cord through the activation of P2X receptors. Nonetheless, the functional significance of postsynaptic P2X receptors in spinal deep dorsal horn neurones is still not yet well understood. Using the whole-cell patch-clamp technique, we investigated whether the activation of postsynaptic P2X receptors can modulate the synaptic transmission in lamina V neurones of postnatal day (P) 9-12 spinal cord slices. At a holding potential of -70 mV, ATPgammaS (100 microm), a nonhydrolysable ATP analogue, generated an inward current, which was resistant to tetrodotoxin (1 microm) in 61% of the lamina V neurones. The ATPgammaS-induced inward current was accompanied by a significant increase in the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in the majority of lamina V neurones. The ATPgammaS-induced inward current was not reproduced by P2Y receptor agonists, UTP (100 microm), UDP (100 microm), and 2-methylthio ADP (100 microm), and it was also not affected by the addition of guanosine-5'-O-(2-thiodiphosphate) (GDPbetaS) into the pipette solution, thus suggesting that ionotropic P2X receptors were activated by ATPgammaS instead of metabotropic P2Y receptors. On the other hand, alpha,beta-methylene ATP (100 microm) did not change any membrane current, but instead increased the mEPSC frequency in the majority of lamina V neurones. The ATPgammaS-induced inward current was suppressed by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) (10 microm), but not by trinitrophenyl-ATP (TNP-ATP) (1 microm). Furthermore, we found that ATPgammaS (100 microm) produced a clear inward current which was observed in all lamina V neurones over P16 spinal cord slices, in contrast to P9-12. These results indicate that distinct subtypes of P2X receptors were functionally expressed at the post- and presynaptic sites in lamina V neurones, both of which may contribute to the hyperexcitability of lamina V in a different manner. In addition, the data relating to the developmental increase in the functional P2X receptors suggest that purinergic signalling may thus be more common in somatosensory transmission with maturation.

Adenosine Triphosphate↗
PubMed2006

Direct GABAergic and glycinergic inhibition of the substantia gelatinosa from the rostral ventromedial medulla revealed by in vivo patch-clamp analysis in rats.

Stimulation of the rostral ventromedial medulla (RVM) is believed to exert analgesic effects through the activation of the serotonergic system descending to the spinal dorsal horn; however, how nociceptive transmission is modulated by the descending system has not been fully clarified. To investigate the inhibitory mechanisms affected by the RVM, an in vivo patch-clamp technique was used to record IPSCs from the substantia gelatinosa (SG) of the spinal cord evoked by chemical (glutamate injection) and electrical stimulation (ES) of the RVM in adult rats. In the voltage-clamp mode, the RVM glutamate injection and RVM-ES produced an increase in both the frequency and amplitude of IPSCs in SG neurons that was not blocked by glutamate receptor antagonists. Serotonin receptor antagonists were unexpectedly without effect, but a GABAA receptor antagonist, bicuculline, or a glycine receptor antagonist, strychnine, completely suppressed the RVM stimulation-induced increase in IPSCs. The RVM-ES-evoked IPSCs showed fixed latency and no failure at 20 Hz stimuli with a conduction velocity of >3 m/s (3.1-20.7 m/s), suggesting descending monosynaptic GABAergic and/or glycinergic inputs from the RVM to the SG through myelinated fibers. In the current-clamp mode, action potentials elicited by noxious mechanical stimuli applied to the receptive field of the ipsilateral hindlimb were suppressed by the RVM-ES in more than half of the neurons tested (63%; 10 of 16). These findings suggest that the RVM-mediated antinociceptive effects on noxious inputs to the SG may be exerted preferentially by the direct GABAergic and glycinergic pathways to the SG.

Animals↗
PubMed2006

Changes in properties of substantia gelatinosa neurons after surgical incision in the rat: in vivo patch-clamp analysis.

BACKGROUND: Noxious information through A delta 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.

Action Potentials↗
PubMed2006

Brain cytokines and the 5-HT system during poly I:C-induced fatigue.

Fatigue is evoked not only by peripheral factors, such as muscle fatigue, but also by the central nervous system (CNS). For example, it is generally known that the feeling of fatigue is greatly influenced by psychological aspects, such as motivation. However, little is known about the central mechanisms of fatigue. The clinical symptoms of chronic fatigue syndrome (CFS) are shown to include disorders in neuroendocrine, autonomic, and immune systems. On the other hand, it has been demonstrated that cytokines produced in the brain play significant roles in neural-immune interactions through their various central actions, including hypothalamo-pituitary and sympathetic activation, as well as immunosuppression. In this article, using the immunologically induced fatigue model, which was achieved by intraperitoneal (i.p.) injection of synthetic double-stranded RNAs, polyriboinosinic: polyribocytidylic acid (poly I:C) in rats, we show an involvement of brain interferon-alpha (IFN-alpha) and serotonin (5-HT) transporter (5-HTT) in the central mechanisms of fatigue. In the poly I:C-induced fatigue rats, expression of IFN-alpha and 5-HTT increased, while extracellular concentration of 5-HT in the medial prefrontal cortex decreased, probably on account of the enhanced expression of 5-HTT. Since the poly I:C-induced reduction of the running wheel activity was attenuated by a 5-HT(1A) receptor agonist, but not by 5-HT(2), 5-HT(3), or dopamine D(3) receptor agonists, it is suggested that the decrease in 5-HT actions on 5-HT(1A) receptors may at least partly contribute to the poly I:C-induced fatigue.

Animals↗
PubMed2005

Feed-forward inhibition: a novel cellular mechanism for the analgesic effect of substance P.

Substance P (SP) is a neuropeptide well known for its contribution to pain transmission in the spinal cord, however, less is known about the possible modulatory effects of SP. A new study by Gu and colleagues, published in Molecular Pain (2005, 1:20), describes its potential role in feed-forward inhibition in lamina V of the dorsal horn of the spinal cord. This inhibition seems to function through a direct excitation of GABAergic interneurons by substance P released from primary afferent fibers and has a distinct temporal phase of action from the well-described glutamate-dependent feed-forward inhibition. It is believed that through this inhibition, substance P can balance nociceptive output from the spinal cord.

Afferent Pathways↗
PubMed2005

Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat.

The aim of the current study was to investigate whether, and if so how, brain-derived neurotrophic factor (BDNF) acts to develop the spinal sensitization underlying inflammation-induced hyperalgesia. In spinal cord slice preparations from rats with inflammation induced by complete Freund's adjuvant (CFA), BDNF, but not nerve growth factor (NGF) or neurotrophin-3 (NT-3), acted presynaptically to increase the frequency of excitatory miniature EPSCs in substantia gelatinosa (SG) neurones of the CFA-treated, but not untreated rats, through activation of lidocaine (lignocaine)-sensitive, TTX-resistant Na+ channels. This effect was observed in the spinal cord slices of the CFA-treated rat only 2-4 days after the CFA injection. On the other hand, the number of monosynaptic Abeta afferent inputs to the SG significantly increased 1 week after the onset of the inflammation, and this increase was significantly suppressed by treatment with anti-BDNF antiserum administered 1 day before and just after the CFA injection. In addition, the treatment with anti-BDNF antiserum significantly attenuated the CFA-induced hyperalgesia and/or allodynia. These findings, taken together, suggest that BDNF, which is considered to be released from the sensitized primary afferents, increases the excitability of SG neurones through its action on the presynaptic terminals. BDNF may thereafter induce monosynaptic Abeta afferents to the SG, thereby developing hyperalgesia and/or allodynia during inflammation.

Animals↗
PubMed2005

Direct inhibition of substantia gelatinosa neurones in the rat spinal cord by activation of dopamine D2-like receptors.

Dopaminergic innervation of the spinal cord is largely derived from the brain. To understand the cellular mechanisms of antinociception mediated by descending dopaminergic pathways, we examined the actions of dopamine (DA) on nociceptive transmission by using behavioural studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurones in the spinal cord. Intrathecal administration of DA increased the mechanical nociceptive threshold and this effect was mimicked by a D2-like receptor agonist, quinpirole, but not by a D1-like receptor agonist, SKF 38393. In current-clamp mode of patch-clamp recordings, bath application of DA hyperpolarized the membrane potential of SG neurones and suppressed action potentials evoked by electrical stimulation of a dorsal root. In voltage-clamp mode, DA induced an outward current that was resistant to TTX, was blocked by the addition of Cs+ or GDP-beta-S in the pipette solution, and was inhibited in the presence of Ba+. The DA-induced current reversed its polarity at a potential close to the equilibrium potential of the K+ channel calculated from the Nernst equation. The DA-induced outward current was mimicked by quinpirole, but not by SKF 38393. The DA-induced outward current was suppressed by a D2-like receptor antagonist, sulpiride, but not by a D1-like receptor antagonist, SCH 23390. In contrast, DA did not cause any significant change in amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). These results indicate that DA mainly acts on postsynaptic SG neurones to induce an outward current via G-protein-mediated activation of K+ channels through D2-like receptors. This may be a possible mechanism for antinociception by the descending dopaminergic pathway.

Action Potentials↗
PubMed2005

Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation.

Transcutaneous sine-wave stimuli at frequencies of 2000, 250 and 5 Hz (Neurometer) are thought to selectively activate Abeta, Adelta and C afferent fibers, respectively. However, there are few reports to test the selectivity of these stimuli at the cellular level. In the present study, we analyzed action potentials (APs) generated by sine-wave stimuli applied to the dorsal root in acutely isolated rat dorsal root ganglion (DRG) preparations using intracellular recordings. We also measured excitatory synaptic responses evoked by transcutaneous stimuli in substantia gelatinosa (SG) neurons of the spinal dorsal horn, which receive inputs predominantly from C and Adelta fibers, using in vivo patch-clamp recordings. In behavioral studies, escape or vocalization behavior of rats was observed with both 250 and 5 Hz stimuli at intensity of approximately 0.8 mA (T5/ T250), whereas with 2000 Hz stimulation, much higher intensity (2.14 mA, T2000) was required. In DRG neurons, APs were generated at T5/T250 by 2000 Hz stimulation in Abeta, by 250 Hz stimulation both in Abeta and Adelta, and by 5 Hz stimulation in all three classes of DRG neurons. However, the AP frequencies elicited in Abeta and Adelta by 5 Hz stimulation were much less than those reported previously in physiological condition. With in vivo experiments large amplitude of EPSCs in SG neurons were elicited by 250 and 5 Hz stimuli at T5/ T250. These results suggest that 2000 Hz stimulation excites selectively Abeta fibers and 5 Hz stimulation activates noxious transmission mediated mainly through C fibers. Although 250 Hz stimulation activates both Adelta and Abeta fibers, tactile sensation would not be perceived when painful sensation is produced at the same time. Therefore, 250 Hz was effective stimulus frequency for activation of Adelta fibers initiating noxious sensation. Thus, the transcutaneous sine-wave stimulation can be applied to evaluate functional changes of sensory transmission by comparing thresholds with the three stimulus frequencies.

Animals↗
PubMed2005

Modulation of glutamate-induced outward current by prostaglandin E(2) in rat dissociated preoptic neurons.

The preoptic/anterior hypothalamus (POA) is one of the major brain regions where cytokines and their related mediators (i.e., prostaglandins) exert diverse actions. In the present study, the modulatory effects of prostaglandin E(2) (PGE(2)) on the glutamate-induced membrane currents were examined using perforated-patch clamp method in rat POA neurons that had been mechanically dissociated by vibration without enzyme treatment. Application of glutamate through U-tube induced a slow outward current following fast inward ionotroic current at a holding membrane potential of -30 mV. The slow outward current was also induced by N-methyl-d-aspartate (NMDA), accompanied by an increased membrane conductance, and inhibited by perfusion with Ca(2+)-free solution, tetraethylammonium chloride (TEA), and apamin, suggesting a Ca(2+)-dependent K(+) current (KCa) activated by Ca(2+) entry through NMDA channels. Perfusion with PGE(2) at 0.1-10 microM, a principal mediator of fever and neuroendocrine control at the POA, did not produce apparent current by itself, but selectively potentiated the glutamate- or NMDA-induced KCa without affecting inward currents. The KCa induced by activation of NMDA receptors may serve as a feedback mechanism and the modulatory effects of PGE(2) on the KCa may have an important physiological significance.

Animals↗
PubMed2005

Molecular pain, a new era of pain research and medicine.

Molecular pain is a relatively new and rapidly expanding research field that represents an advanced step from conventional pain research. Molecular pain research addresses physiological and pathological pain at the cellular, subcellular and molecular levels. These studies integrate pain research with molecular biology, genomics, proteomics, modern electrophysiology and neurobiology. The field of molecular pain research has been rapidly expanding in the recent years, and has great promise for the identification of highly specific and effective targets for the treatment of intractable pain. Although several existing journals publish articles on classical pain research, none are specifically dedicated to molecular pain research. Therefore, a new journal focused on molecular pain research is needed. Molecular Pain, an Open Access, peer-reviewed, online journal, will provide a forum for molecular pain scientists to communicate their research findings in a targeted manner to others in this important and growing field.

Biomedical Research↗
PubMed2005

Enhanced expression of brain interferon-alpha and serotonin transporter in immunologically induced fatigue in rats.

Immunologically induced fatigue was induced in rats by intraperitoneal injection of a synthetic double-stranded RNA, polyriboinosinic : polyribocytidylic acid (poly I:C). An injection of poly I:C (3 mg/kg) decreased the daily amounts of spontaneous running wheel activity to approximately 60% of the preinjection level until day 8. Quantitative analysis of mRNA levels demonstrated that interferon-alpha (IFN-alpha) and p38 mitogen-activated protein kinase mRNAs increased in the medial preoptic, paraventricular and ventromedial hypothalamic nuclei and in cortex on both days 1 and 8, while interleukin-1beta and an inhibitor of nuclear factor kappaB (IkappaB)-beta mRNAs increased on day 1, but recovered within a week. Serotonin transporter (5-HTT) mRNA also increased on days 1 and 8 after poly I:C injection in the same brain regions where IFN-alpha mRNA increased. The increased 5-HTT had a functional significance, because in vivo brain microdialysis revealed that an i.p. injection of poly I:C induced a decrease in the extracellular concentration of 5-HT in the prefrontal cortex; the decrease was blocked by local perfusion with a nonselective 5-HT reuptake inhibitor, imipramine. Finally, the poly I:C-induced fatigue was attenuated by a 5-HT1A receptor agonist but not by 5-HT2, 5-HT3 or dopamine D3 agonists. These findings, taken together, suggest that disorders in brain IFN-alpha and 5-HTT expression may be involved in the neuronal mechanisms of the poly I:C-induced fatigue.

Animals↗
PubMed2005

In vivo and in vitro patch-clamp recording analysis of the process of sensory transmission in the spinal cord and sensory cortex.

Following the integration and modification of the sensory inputs in the spinal cord, the information is transmitted to the primary sensory cortex where the integrated information is further processed and perceived. Processing of the sensory information in the spinal cord has been intensively investigated. However, the mechanisms of how the inputs are processed in the cortex are still unclear. To know the correlation of the sensory processing in the dorsal horn and cortex, in vivo and in vitro patch-clamp recordings were made from rat dorsal horn and sensory cortex. Although dorsal horn neurons showed spontaneous and evoked EPSCs by noxious and non-noxious stimuli, most somatosensory neurons located at 100 to 1000 microm from the surface of the cortex exhibited an oscillatory activity and received synaptic inputs from non-noxious but not noxious receptors. These observations suggest that the synaptic responses in cortical neurons are processed in a more complex manner; and this may be due to the reciprocal synaptic connection between thalamus and cortex.

Animals↗
PubMed2005

[Spinal anti-nociceptive effect of calcitonin in an osteoporotic model rat--functional recovery of descending serotonergic inhibition].

Although calcitonin is generally used to relieve chronic pain accompanying osteoporosis, little is known about what kind of noxious sensation is alleviated by calcitonin. We examined actions of calcitonin on nociceptive transmission in the spinal dorsal horn of ovariectomized (OVX) rats using in vivo patch-clamp technique. Inhibitory effect of serotonin on mechanical noxious inputs to dorsal horn neurons was reduced in OVX rats. This mechanical hyperalgesia observation in OVX rats was attenuated by calcitonin treatment.

Animals↗