Publications by authors named "Hidemasa Furue"

77 Publications

Anesthesia and surgery induce a functional decrease in excitatory synaptic transmission in prefrontal cortex neurons, and intraoperative administration of dexmedetomidine does not elicit the synaptic dysfunction.

Biochem Biophys Res Commun 2021 Oct 29;572:27-34. Epub 2021 Jul 29.

Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address:

Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. The prefrontal cortex (PFC) plays key roles in executive functions and cognitive controls. However, the neuropathogenesis of POD in the PFC remains largely unknown. We investigated whether anesthesia and surgery induced neurofunctional changes in the mouse PFC. After laparotomy was performed under isoflurane anesthesia, PFC neuronal activities were compared at the synaptic level using whole-cell patch-clamp recordings. A battery of behavioral tests measuring natural and learned behaviors, and effects of intraoperative dexmedetomidine were also examined. In the anesthesia/surgery group showing changes in natural and learned behaviors, the frequency of excitatory synaptic responses in PFC pyramidal neurons was decreased after the surgery without any changes in the response kinetics. On the other hand, neuronal intrinsic properties and inhibitory synaptic responses were not changed. In the anesthesia/surgery group administered intraoperative dexmedetomidine, the excitatory synaptic transmission and the behaviors were not altered. These results suggest that anesthesia and surgery induce a functional reduction selectively in the PFC excitatory synaptic transmission, and intraoperative dexmedetomidine inhibits the plastic change in the PFC excitatory synaptic input.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.07.065DOI Listing
October 2021

A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior.

Proc Natl Acad Sci U S A 2021 01;118(3)

Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 812-8582 Fukuoka, Japan;

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP) and show that specific ablation or silencing of AAV-NpyP SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses. AAV-NpyP neurons received excitatory inputs from Aβ fibers and transmitted inhibitory GABA signals to lamina I neurons projecting to the brain. In a model of neuropathic pain developed by peripheral nerve injury, AAV-NpyP neurons exhibited deeper resting membrane potentials, and their excitation by Aβ fibers was impaired. Conversely, chemogenetic activation of AAV-NpyP neurons in nerve-injured rats reversed Aβ fiber-derived neuropathic pain-like behavior that was shown to be morphine-resistant and reduced pathological neuronal activation of superficial SDH including lamina I. These findings suggest that identified inhibitory SDH interneurons that act as a critical brake on conversion of touch-sensing Aβ fiber signals into pain-like behavioral responses. Thus, enhancing activity of these neurons may offer a novel strategy for treating neuropathic allodynia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2021220118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826356PMC
January 2021

Correction to: Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex.

Mol Brain 2020 Nov 13;13(1):152. Epub 2020 Nov 13.

Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

An amendment to this paper has been published and can be accessed via the original article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13041-020-00692-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664103PMC
November 2020

L-bupivacaine Inhibition of Nociceptive Transmission in Rat Peripheral and Dorsal Horn Neurons.

Anesthesiology 2021 01;134(1):88-102

Background: Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified.

Methods: The authors performed electrophysiologic analysis on rat dorsal root ganglion neurons in vitro and on spinal transmissions in vivo.

Results: In the dorsal root ganglion, these anesthetics decreased the amplitudes of action potentials. The half-maximum inhibitory concentrations of D-enantiomer D-bupivacaine were almost equal for Aβ (29.5 μM), Aδ (29.7μM), and C (29.8 μM) neurons. However, the half-maximum inhibitory concentrations of L-bupivacaine was lower for Aδ (19.35 μM) and C (19.5 μM) neurons than for A β (79.4 μM) neurons. Moreover, D-bupivacaine almost equally inhibited tetrodotoxin-resistant (mean ± SD: 15.8 ± 10.9% of the control, n = 14, P < 0.001) and tetrodotoxin-sensitive (15.4 ± 15.6% of the control, n = 11, P = 0.004) sodium currents. In contrast, L-bupivacaine suppressed tetrodotoxin-resistant sodium currents (26.1 ± 19.5% of the control, n = 18, P < 0.001) but not tetrodotoxin-sensitive sodium currents (74.5 ± 18.2% of the control, n = 11, P = 0.477). In the spinal dorsal horn, L-bupivacaine decreased the area of pinch-evoked excitatory postsynaptic currents (39.4 ± 11.3% of the control, n = 7, P < 0.001) but not touch-evoked responses (84.2 ± 14.5% of the control, n = 6, P = 0.826). In contrast, D-bupivacaine equally decreased pinch- and touch-evoked responses (38.8 ± 9.5% of the control, n = 6, P = 0.001, 42.9 ± 11.8% of the control, n = 6, P = 0.013, respectively).

Conclusions: These results suggest that the L-enantiomer of bupivacaine (L-bupivacaine) effectively inhibits noxious transmission to the spinal dorsal horn by blocking action potential conduction through C and Aδ afferent fibers.

Editor’s Perspective:
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ALN.0000000000003596DOI Listing
January 2021

Involvement of cannabinoid type 1 receptor in fasting-induced analgesia.

Mol Pain 2020 Jan-Dec;16:1744806920969476

Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.

The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.) administration of CB1R antagonist (SR 141716). In the present study, we further examined the effect of CB1R expressed in the peripheral tissues. In the formalin-induced inflammatory pain model, i.p. administration of peripherally restricted CB1R antagonist (AM 6545) reversed fasting-induced analgesia. However, intraplantar administration of SR 141716 did not affect fasting-induced analgesia. Furthermore, mRNA expression of CB1R did not change in the formalin model by fasting in the dorsal root ganglia. The formalin-induced c-Fos expression at the spinal cord level was not affected by fasting, and recording from the superficial dorsal horn of the lumbar spinal cord revealed that fasting did not affect formalin-induced neural activity, which indicates minimal involvement of the spinal cord in fasting-induced analgesia. Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1744806920969476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607739PMC
July 2021

Anti-nociceptive and anxiolytic effects of systemic flupirtine and its direct inhibitory actions on in vivo neuronal mechanical sensory responses in the adult rat anterior cingulate cortex.

Biochem Biophys Res Commun 2020 10 14;531(4):528-534. Epub 2020 Aug 14.

Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan. Electronic address:

Flupirtine is a non-opioid centrally acting analgesic that has been in clinical use, and is reported to act on neuronal ion channels and neurotransmitter receptors. However, its action on emotional aspects of pain is still unknown. In this study, we examined whether flupirtine has anxiolytic action and assayed its direct actions on the anterior cingulate cortex (ACC) at the single neuronal and synaptic levels. Anti-nociceptive and anxiolytic effects of flupirtine were evaluated by von Frey test and elevated plus-maze (EPM) in adult rats. The effects of flupirtine on firings and synaptic currents in the rat ACC were examined using in vivo extracellular and brain slice patch-clamp recording techniques, respectively. Systemic administration of flupirtine increased paw withdrawal threshold, and reduced anxiety-like behavior in the EPM. ACC neurons fired spontaneously. Mechanical stimulation of the contralateral hind paw with the von Frey filaments increased firing from the basal spontaneous activity. Intravenous administration of flupirtine reduced both spontaneous and stimulus-evoked firing frequency in the ACC. Flupirtine microinjected into the ACC also inhibited the spontaneous and evoked-responses. In brain slices, flupirtine did not induce any detectable outward currents, but it prolonged the decay time of GABAergic inhibitory synaptic responses. These results suggest that flupirtine directly augments GABAergic synaptic currents and suppresses evoked mechanical nociceptive responses in the ACC. This direct action in the ACC may reduce emotional aspect of pain and induce anxiolytic action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.07.129DOI Listing
October 2020

Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex.

Mol Brain 2020 03 26;13(1):49. Epub 2020 Mar 26.

Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

Anterior cingulate cortex (ACC) plays important roles in sensory perception including pain and itch. Neurons in the ACC receive various neuromodulatory inputs from subcortical structures, including locus coeruleus noradrenaline (LC-NA) neurons. Few studies have been reported about synaptic and behavioral functions of LC-NA projections to the ACC. Using viral-genetic method (AAV-DIO-eYFP) on DBH-cre mice, we found that LC-NA formed synaptic connections to ACC pyramidal cells but not interneurons. This is further supported by the electron microscopic study showing NAergic fibers contact the presynaptic inputs and post-synaptic areas of the pyramidal cells. NA application produced both pre- and post-synaptic potentiation effects in ACC excitatory transmission in vivo and in vitro. Activation of LC-NA projection to the ACC by optogenetic method produced enhancement of excitatory transmission in vitro and induced scratching and behavioral sensitization for mechanical stimulation. Our results demonstrate that LC-NA projections enhance or facilitate brain responses to pain and itch by potentiating glutamatergic synaptic transmissions in the ACC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13041-020-00586-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098117PMC
March 2020

Responsiveness of lumbosacral superficial dorsal horn neurons during the voiding reflex and functional loss of spinal urethral-responsive neurons in streptozotocin-induced diabetic rats.

Neurourol Urodyn 2020 01 29;39(1):144-157. Epub 2019 Oct 29.

Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan.

Aims: Sensory information from the lower urinary tract (LUT) is conveyed to the spinal cord to trigger and co-ordinate micturition. However, it is not fully understood how spinal dorsal horn neurons are excited during the voiding reflex. In this study, we developed an in vivo technique allowing recording of superficial dorsal horn (SDH) neurons concurrent with intravesical pressure (IVP) during the micturition cycle in both normal and diabetic rats.

Methods: Lumbosacral dorsal horn neuronal activity and IVP were recorded from urethane-anesthetized naive and streptozotocin (STZ)-induced diabetic rats. Saline was continuously perfused into the urinary bladder through a cannula to induce micturition.

Results: We classified SDH neurons into bladder- and urethral-responsive neurons, based on their responsiveness during the voiding reflex. Bladder-responsive SDH neurons responded to the rapid increase in IVP at the start of voiding. In contrast, urethral-responsive SDH neuronal firing increased at the peak IVP and their firing lasted during the voiding phase (the high-frequency oscillations). Urethral-responsive SDH neurons were more sensitive to capsaicin, received C afferent fiber inputs, and were rarely detected in STZ-diabetes rats. Administration of a cyclohexenoic long-chain fatty alcohol (TAC-302), which is reported to promote neurite outgrowth of peripheral nerves in STZ-diabetic rats, prevented the functional loss of spinal urethral response.

Conclusions: Sensory information from the bladder and urethra is conveyed separately to different groups of SDH neurons. Functional loss of spinal urethral sensory information through unmyelinated C afferent fibers may contribute to diabetic bladder dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nau.24198DOI Listing
January 2020

Roles of the noradrenergic nucleus locus coeruleus and dopaminergic nucleus A11 region as supraspinal defecation centers in rats.

Am J Physiol Gastrointest Liver Physiol 2019 10 28;317(4):G545-G555. Epub 2019 Aug 28.

Department of Basic Veterinary Science, Laboratory of Physiology, United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.

We previously demonstrated that administration of norepinephrine, dopamine, and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are released mainly from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles of the noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex. Colorectal motility was measured with a balloon in anesthetized rats. Electrical stimulation of the LC and A11 region increased colorectal pressure only when a GABA receptor antagonist was injected into the lumbosacral spinal cord. The effects of the LC stimulation and A11 region stimulation on colorectal motility were inhibited by antagonists of α1-adrenoceptors and D2-like dopamine receptors injected into the lumbosacral spinal cord, respectively. Spinal injection of a norepinephrine-dopamine reuptake inhibitor augmented the colokinetic effect of LC stimulation. The effect of stimulation of each nucleus was abolished by surgical severing of the parasympathetic pelvic nerves. Our findings demonstrate that activation of descending noradrenergic neurons from the LC and descending dopaminergic neurons from the A11 region causes enhancement of colorectal motility via the lumbosacral defecation center. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers. The present study demonstrates that electrical and chemical stimulations of the locus coeruleus or A11 region augment contractions of the colorectum. The effects of locus coeruleus and A11 stimulations on colorectal motility are due to activation of α1-adrenoceptors and D2-like dopamine receptors in the lumbosacral defecation center, respectively. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpgi.00062.2019DOI Listing
October 2019

Ethanol-induced enhancement of inhibitory synaptic transmission in the rat spinal substantia gelatinosa.

Mol Pain 2018 Jan-Dec;14:1744806918817969. Epub 2018 Nov 19.

1 Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan.

Recent studies have shown that ethanol produces a widespread modulation of neuronal activity in the central nervous system. It is not fully understood, however, how ethanol changes nociceptive transmission. We investigated acute effects of ethanol on synaptic transmission in the substantia gelatinosa (lamina II of the spinal dorsal horn) and mechanical responses in the spinal dorsal horn. In substantia gelatinosa neurons, bath application of ethanol at low concentration (10 mM) did not change the frequency and amplitude of spontaneous inhibitory postsynaptic currents. At medium to high concentrations (20-100 mM), however, ethanol elicited a barrage of large amplitude spontaneous inhibitory postsynaptic currents. In the presence of tetrodotoxin, such enhancement of spontaneous inhibitory postsynaptic currents was not detected. In addition, ethanol (20-100 mM) increased the frequency of spontaneous discharge of vesicular GABA transporter-Venus-labeled neurons and suppressed the mechanical nociceptive response in wide-dynamic range neurons in the spinal dorsal horn. The present results suggest that ethanol may reduce nociceptive information transfer in the spinal dorsal horn by enhancement of inhibitory GABAergic and glycinergic synaptic transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1744806918817969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293375PMC
April 2019

Stimulating muscarinic M receptors in the anterior cingulate cortex reduces mechanical hypersensitivity via GABAergic transmission in nerve injury rats.

Brain Res 2019 02 17;1704:187-195. Epub 2018 Oct 17.

Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan. Electronic address:

Cholinergic systems modulate synaptic transmission across the neuraxis and play an important role in higher brain function including cognition, arousal and nociception. The anterior cingulate cortex (ACC) is a fundamental brain region for nociception and chronic pain, and receives cholinergic projections mainly from basal forebrain. Recently, we found that the activation of muscarinic M receptors in the ACC produced antinociceptive behavior in response to mechanical stimulation. However, it has not been tested whether stimulating muscarinic receptors in the ACC can reduce mechanical hypersensitivity in animal models of chronic pain. Here, we tested whether the activation of muscarinic M receptors in the ACC can alleviate mechanical hypersensitivity in a nerve injury model. The activation of muscarinic M/M receptors by McN-A-343 injected into the contralateral side of the ACC, but not into the ventral posterolateral nucleus, was found to dose-dependently reduce mechanical hypersensitivity 7 days following partial sciatic nerve ligation in rats. The reduction of mechanical hypersensitivity by McN-A-343, was blocked by a selective muscarinic M antagonist, but not a M receptor antagonist. Importantly, the nerve injury model did not change the protein expression of muscarinic M receptors in the ACC. Additionally, a type A γ-aminobutyric acid (GABA) receptor agonist injected into the ACC reduced the mechanical hypersensitivity in this injury model. Finally, a GABA receptor antagonist blocked the reduction of mechanical hypersensitivity by McN-A-343 in the injury model. Collectively, these results suggest that activations of muscarinic M receptors in the ACC reduce nerve injury-induced mechanical hypersensitivity through GABAergic transmission via GABA receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2018.10.013DOI Listing
February 2019

Chronic inflammatory pain induced GABAergic synaptic plasticity in the adult mouse anterior cingulate cortex.

Mol Pain 2018 Jan-Dec;14:1744806918783478. Epub 2018 Jun 29.

1 Department of Neurophysiology, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan.

Background Chronic pain is a persistent unpleasant sensation that produces pathological synaptic plasticity in the central nervous system. Both human imaging study and animal studies consistently demonstrate that the anterior cingulate cortex is a critical cortical area for nociceptive and chronic pain processing. Thus far, the mechanisms of excitatory synaptic transmission and plasticity have been well characterized in the anterior cingulate cortex for various models of chronic pain. By contrast, the potential contribution of inhibitory synaptic transmission in the anterior cingulate cortex, in models of chronic pain, is not fully understood. Methods Chronic inflammation was induced by complete Freund adjuvant into the adult mice left hindpaw. We performed in vitro whole-cell patch-clamp recordings from layer II/III pyramidal neurons in two to three days after the complete Freund adjuvant injection and examined if the model could cause plastic changes, including transient and tonic type A γ-aminobutyric acid (GABA) receptor-mediated inhibitory synaptic transmission, in the anterior cingulate cortex. We analyzed miniature/spontaneous inhibitory postsynaptic currents, GABA receptor-mediated tonic currents, and evoked inhibitory postsynaptic currents. Finally, we studied if GABAergic transmission-related proteins in the presynapse and postsynapse of the anterior cingulate cortex were altered. Results The complete Freund adjuvant model reduced the frequency of both miniature and spontaneous inhibitory postsynaptic currents compared with control group. By contrast, the average amplitude of these currents was not changed between two groups. Additionally, the complete Freund adjuvant model did not change GABA receptor-mediated tonic currents nor the set of evoked inhibitory postsynaptic currents when compared with control group. Importantly, protein expression of vesicular GABA transporter was reduced within the presynpase of the anterior cingulate cortex in complete Freund adjuvant model. In contrast, the complete Freund adjuvant model did not change the protein levels of GABA receptors subunits such as α1, α5, β2, γ2, and δ. Conclusion Our results suggest that the induction phase of inflammatory pain involves spontaneous GABAergic plasticity at presynaptic terminals of the anterior cingulate cortex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1744806918783478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096674PMC
December 2018

Optogenetic Activation of Non-Nociceptive Aβ Fibers Induces Neuropathic Pain-Like Sensory and Emotional Behaviors after Nerve Injury in Rats.

eNeuro 2018 Jan-Feb;5(1). Epub 2018 Feb 15.

Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Neuropathic pain is caused by peripheral nerve injury (PNI). One hallmark symptom is allodynia (pain caused by normally innocuous stimuli), but its mechanistic underpinning remains elusive. Notably, whether selective stimulation of non-nociceptive primary afferent Aβ fibers indeed evokes neuropathic pain-like sensory and emotional behaviors after PNI is unknown, because of the lack of tools to manipulate Aβ fiber function in awake, freely moving animals. In this study, we used a transgenic rat line that enables stimulation of non-nociceptive Aβ fibers by a light-activated channel (channelrhodopsin-2; ChR2). We found that illuminating light to the plantar skin of these rats with PNI elicited pain-like withdrawal behaviors that were resistant to morphine. Light illumination to the skin of PNI rats increased the number of spinal dorsal horn (SDH) Lamina I neurons positive to activity markers (c-Fos and phosphorylated extracellular signal-regulated protein kinase; pERK). Whole-cell recording revealed that optogenetic Aβ fiber stimulation after PNI caused excitation of Lamina I neurons, which were normally silent by this stimulation. Moreover, illuminating the hindpaw of PNI rats resulted in activation of central amygdaloid neurons and produced an aversion to illumination. Thus, these findings provide the first evidence that optogenetic activation of primary afferent Aβ fibers in PNI rats produces excitation of Lamina I neurons and neuropathic pain-like behaviors that were resistant to morphine treatment. This approach may provide a new path for investigating circuits and behaviors of Aβ fiber-mediated neuropathic allodynia with sensory and emotional aspects after PNI and for discovering novel drugs to treat neuropathic pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0450-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819669PMC
January 2019

Noradrenergic effects in rat sacral autonomic nucleus using in vitro slice patch-clamp recordings.

Biomed Res 2017 ;38(6):359-369

Department of Neurophysiology, Akita University, School of Medicine.

Noradrenergic modulation has been frequently discussed in the context of neural activities that are related to pelvic organs. The sacral preganglionic nucleus (SPN) is a spinal nucleus containing parasympathetic preganglionic neurons that send fibers to pelvic nerves. In spite of the abundant presence of noradrenergic fibers around the SPN, the effects of noradrenaline (NA) remain obscure. To explore this issue, NA (50 μM) was applied to parasympathetic preganglionic neurons in the SPN during whole-cell patch clamp recording. The SPN was labeled with the retrograde tracer, DiI. These neurons demonstrated two classes of firing patterns (delayed and regular) in terms of initiation of firing. Independent of these firing patterns, NA induced inward (56%) or outward (32%) currents in labeled SPN neurons. Phenylephrine, an α1 receptor agonist, induced an inward current, and clonidine, an α2 receptor agonist, induced an outward current, indicating the existence of both α1 and α2 adrenoreceptors in DiI-labeled SPN neurons. NA also modulated synaptic currents according to the firing patterns. In delayed firing neurons, NA inhibited both spontaneous excitatory post-synaptic currents (sEPSCs) and spontaneous inhibitory post-synaptic currents (sIPSCs). Hence, NA facilitated sEPSCs and sIPSCs in about a half of regular firing neurons. Bath application of phenylephrine facilitated sEPSCs and sIPSCs, and clonidine inhibited them. These results support the hypothesis of multiple effects of NA in the SPN, and may suggest functional differences among SPN neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2220/biomedres.38.359DOI Listing
July 2018

Medullary raphe nuclei activate the lumbosacral defecation center through the descending serotonergic pathway to regulate colorectal motility in rats.

Am J Physiol Gastrointest Liver Physiol 2018 03 22;314(3):G341-G348. Epub 2017 Nov 22.

Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University , Gifu , Japan.

Colorectal motility is regulated by two defecation centers located in the brain and spinal cord. In previous studies, we have shown that administration of serotonin (5-HT) in the lumbosacral spinal cord causes enhancement of colorectal motility. Because spinal 5-HT is derived from neurons of the medullary raphe nuclei, including the raphe magnus, raphe obscurus, and raphe pallidus, we examined whether stimulation of the medullary raphe nuclei enhances colorectal motility via the lumbosacral defecation center. Colorectal pressure was recorded with a balloon in vivo in anesthetized rats. Electrical stimulation of the medullary raphe nuclei failed to enhance colorectal motility. Because GABAergic neurons can be simultaneously activated by the raphe stimulation and released GABA masks accelerating actions of the raphe nuclei on the lumbosacral defecation center, a GABA receptor antagonist was preinjected intrathecally to manifest excitatory responses. When spinal GABA receptors were blocked by the antagonist, electrical stimulation of the medullary raphe nuclei increased colorectal contractions. This effect of the raphe nuclei was inhibited by intrathecal injection of 5-hydroxytryptamine type 2 (5-HT) and type 3 (5-HT) receptor antagonists. In addition, injection of a selective 5-HT reuptake inhibitor in the lumbosacral spinal cord augmented the raphe stimulation-induced enhancement of colorectal motility. Transection of the pelvic nerves, but not transection of the colonic nerves, prevented the effect of the raphe nuclei on colorectal motility. These results demonstrate that activation of the medullary raphe nuclei causes augmented contractions of the colorectum via 5-HT and 5-HT receptors in the lumbosacral defecation center. NEW & NOTEWORTHY We have shown that electrical stimulation of the medullary raphe nuclei causes augmented contractions of the colorectum via pelvic nerves in rats. The effect of the medullary raphe nuclei on colorectal motility is exerted through activation of 5-hydroxytryptamine type 2 and type 3 receptors in the lumbosacral defecation center. The descending serotoninergic raphespinal tract represents new potential therapeutic targets against colorectal dysmotility such as irritable bowel syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpgi.00317.2017DOI Listing
March 2018

Impaired peripheral nerve regeneration in type-2 diabetic mouse model.

Eur J Neurosci 2018 01 11;47(2):126-139. Epub 2018 Jan 11.

Department of Medical Chemistry, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.

Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.13771DOI Listing
January 2018

Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours.

Sci Rep 2017 07 5;7(1):4739. Epub 2017 Jul 5.

Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Inhibitory interneurons in the spinal dorsal horn (SDH) are crucial for processing somatosensory information originating in the periphery. However, the effects of the acute and selective inactivation of GABAergic SDH interneurons on pain processing are not fully understood. In this study, we used designer receptors exclusively activated by designer drugs (DREADD) technology and vesicular GABA transporter-Cre (Vgat-Cre) mice to selectively express a modified human muscarinic Gi protein-coupled receptor (hM4Di) in Vgat-Cre GABAergic SDH interneurons in the fourth lumbar segment. We found that clozapine-N-oxide (CNO) treatment rapidly hyperpolarized these neurons and induced spontaneous nocifensive behaviours in these mice. In Vgat-Cre lamina II neurons, CNO produced facilitation of A fibre-mediated polysynaptic excitatory responses, an effect that required N-methyl-D-aspartate (NMDA) receptor activation. The CNO-induced nocifensive behaviours were also reduced by NMDA receptor antagonism. Moreover, these nocifensive behaviours were suppressed by pregabalin but resistant to morphine. Our findings indicate that Vgat-Cre SDH interneurons play an important role in morphine-resistant nocifensive behaviours and suggest that this approach may provide a useful model for understanding the mechanisms of opioid-resistant pain signalling and for developing novel analgesics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-04972-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498492PMC
July 2017

Characterization of Nociceptive Behaviors Induced by Formalin in the Glabrous and Hairy Skin of Rats.

Basic Clin Neurosci 2017 Jan;8(1):37-42

Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, Japan.

Introduction: Glabrous skin and hairy skin are innervated by different types of noxious fibers. However, the different nociceptive behaviors induced by formalin, a commonly used model of acute inflammatory pain, have not yet been systematically examined in the glabrous and hairy skin.

Methods: In this study, we compared nociceptive behaviors induced by formalin injections (2%, 4%, and 8%) into either glabrous skin (plantar surface) of the hind paw or hairy skin of the hind limb in adult rats.

Results: A typical biphasic nociceptive response was seen after formalin injection into the plantar surface of the hind paw. A brief interphase separates the first and second phases where nociceptive behaviors were barely spotted. However, following subcutaneous injection into the hairy skin nociceptive behaviors were only seen after 10 minutes of formalin injection, which correlates in time with the second phase of the formalin response. First phase nociceptive behaviors were never seen with hairy skin injection, even following multiple injections of formalin.

Conclusion: These data suggest that nociceptive behaviors and spinal responses induced by formalin injections to glabrous and hairy skin areas are different, and that the first and second phases may be mediated through different noxious afferent fibers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15412/J.BCN.03080105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396171PMC
January 2017

Acute inflammation reveals GABA receptor-mediated nociception in mouse dorsal root ganglion neurons via PGE receptor 4 signaling.

Physiol Rep 2017 Apr;5(8)

Pain Laboratory, Dental Research Institute and Department of Neurobiology and Physiology School of Dentistry Seoul National University, Seoul, Korea

Gamma-aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl permeable GABA receptors but the physiologic role of GABA receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABA receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABA receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre-conditioning with formalin but had no effect in saline-treated mice. GABA receptor-mediated pain behavior after acute formalin treatment was abolished by the GABA receptor blocker picrotoxin and cyclooxygenase inhibitor indomethacin. In addition, treatment with prostaglandin E2 (PGE) was sufficient to reveal muscimol-induced licking behavior. In vitro, GABA induced sub-threshold depolarization in DRG neurons through GABA receptor activation. Both formalin and PGE potentiated GABA-induced Ca transients and membrane depolarization in capsaicin-sensitive nociceptive DRG neurons; these effects were blocked by the prostaglandin E2 receptor 4 (EP4) antagonist AH23848 (10 mol/L). Furthermore, potentiation of GABA responses by PGE was prevented by the selective Na1.8 antagonist A887826 (100 nmol/L). Although the function of the Na-K-2Cl co-transporter NKCC1 was required to maintain the Cl ion gradient in isolated DRG neurons, NKCC1 was not required for GABA receptor-mediated nociceptive behavior after acute inflammation. Taken together, these results demonstrate that GABA receptors may contribute to the excitation of peripheral sensory neurons in inflammation through a combined effect involving PGE-EP4 signaling and Na channel sensitization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14814/phy2.13178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408276PMC
April 2017

In vivo electrophysiological analysis of mechanisms of monoaminergic pain inhibitory systems.

Pain 2017 04;158 Suppl 1:S85-S91

Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/j.pain.0000000000000844DOI Listing
April 2017

4-isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1, TRPV1 and TRPA1 channel activities.

Sci Rep 2017 02 22;7:43132. Epub 2017 Feb 22.

Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.

Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects. Here we show that menthol and the menthol analogue isopropylcyclohexane (iPr-CyH) inhibited ANO1 channels in mice. The iPr-CyH derivative 4-isopropylcyclohexanol (4-iPr-CyH-OH) inhibited mouse ANO1 currents more potently than iPr-CyH. Moreover, 4-iPr-CyH-OH inhibited the activities of TRPV1, TRP ankyrin 1 (TRPA1), TRP melastatin 8 (TRPM8) and TRPV4. Single-channel analysis revealed that 4-iPr-CyH-OH reduced TRPV1 and TRPA1 current open-times without affecting unitary amplitude or closed-time, suggesting that it affected gating rather than blocking the channel pore. The ability of 4-iPr-CyH-OH to inhibit action potential generation and reduce pain-related behaviors induced by capsaicin in mice suggests that 4-iPr-CyH-OH could have analgesic applications. Thus, 4-iPr-CyH-OH is a promising base chemical to develop novel analgesics that target ANO1 and TRP channels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep43132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320485PMC
February 2017

Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: electrophysiological and behavioral assessments.

J Physiol Sci 2017 May 28;67(3):431-438. Epub 2016 Nov 28.

Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.

We investigated the spinal action of noradrenaline on cold-elicited hyperexcitation detected in dorsal horn neurons of rats with allodynia induced by an oxaliplatin (6 mg/kg, i.p.) injection. In vivo extracellular recordings from the spinal dorsal horn showed that wide dynamic range neurons responded to cutaneous acetone (10 μl) stimulation in normal rats, and cold-elicited firings in oxaliplatin-administered rats were increased with a longer duration, correlated with behavioral responses. These responses were significantly attenuated by spinal administration (50 μM) of noradrenaline or its agonists, clonidine (α), phenylephrine (α) and isoprenaline (β), in descending order of efficacy. Thus, the inhibitory effect of noradrenaline on spinal oxaliplatin-induced cold hyperexcitation is mediated mainly by activation of α- and/or α-adrenoceptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12576-016-0505-9DOI Listing
May 2017

Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury.

eNeuro 2016 Sep-Oct;3(5). Epub 2016 Oct 17.

Department of Medical Chemistry, Kansai Medical University , Hirakata 573-1010, Japan.

Maintenance of neuropathic pain caused by peripheral nerve injury crucially depends on the phosphorylation of GluN2B, a subunit of the N-methyl-d-aspartate (NMDA) receptor, at Tyr1472 (Y1472) and subsequent formation of a postsynaptic density (PSD) complex of superficial spinal dorsal horn neurons. Here we took advantage of comparative proteomic analysis based on isobaric stable isotope tags (iTRAQ) between wild-type and knock-in mice with a mutation of Y1472 to Phe of GluN2B (Y1472F-KI) to search for PSD proteins in the spinal dorsal horn that mediate the signaling downstream of phosphorylated Y1472 GluN2B. Among several candidate proteins, we focused on brain-enriched guanylate kinase-associated protein (BEGAIN), which was specifically up-regulated in wild-type mice after spared nerve injury (SNI). Immunohistochemical analysis using the generated antibody demonstrated that BEGAIN was highly localized at the synapse of inner lamina II in the spinal dorsal horn and that its expression was up-regulated after SNI in wild-type, but not in Y1472F-KI, mice. In addition, alteration of the kinetics of evoked excitatory postsynaptic currents for NMDA but not those for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in spinal lamina II was demonstrated by BEGAIN deletion. We demonstrated that mechanical allodynia, a condition of abnormal pain induced by innocuous stimuli, in the SNI model was significantly attenuated in BEGAIN-deficient mice. However, there was no significant difference between naive wild-type and BEGAIN-knockout mice in terms of physiological threshold for mechanical stimuli. These results suggest that BEGAIN was involved in pathological pain transmission through NMDA receptor activation by the phosphorylation of GluN2B at Y1472 in spinal inner lamina II.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0110-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066261PMC
October 2017

Changes in synaptic transmission of substantia gelatinosa neurons after spinal cord hemisection revealed by analysis using in vivo patch-clamp recording.

Mol Pain 2016 28;12. Epub 2016 Aug 28.

Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Background: After 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.

Results: An 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 frequency of spontaneous inhibitory postsynaptic currents of substantia gelatinosa neurons in hemisected animals were significantly smaller and lower, respectively, than those in control animals (P < 0.01). Large amplitude and high-frequency spontaneous inhibitory postsynaptic currents, which could not be elicited by mechanical stimuli, were seen in 44% of substantia gelatinosa neurons in control animals but only in 17% of substantia gelatinosa neurons in hemisected animals. In control animals, such large amplitude spontaneous inhibitory postsynaptic currents were suppressed by spinal application of tetrodotoxin (1 µM). Cervical application of lidocaine (2%, 10 µl) also inhibited such large amplitude of inhibitory postsynaptic currents. The proportion of multi-receptive substantia gelatinosa neurons, which exhibit action potential firing in response to non-noxious and noxious stimuli, was much larger in hemisected animals than in control animals.

Conclusions: These suggest that substantia gelatinosa neurons receive tonic inhibition by spinal inhibitory interneurons which generate persistent action potentials. Spinal hemisection results in hyperexcitation of substantia gelatinosa neurons at least in part by eliminating the tonic descending control of spinal inhibitory interneurons from supraspinal levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1744806916665827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006296PMC
October 2017

Intravenous administration of lidocaine directly acts on spinal dorsal horn and produces analgesic effect: An in vivo patch-clamp analysis.

Sci Rep 2016 05 18;6:26253. Epub 2016 May 18.

Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, 951-8510 Japan.

Intravenous lidocaine administration produces an analgesic effect in various pain states, such as neuropathic and acute pain, although the underlying mechanisms remains unclear. Here, we hypothesized that intravenous lidocaine acts on spinal cord neurons and induces analgesia in acute pain. We therefore examined the action of intravenous lidocaine in the spinal cord using the in vivo patch-clamp technique. We first investigated the effects of intravenous lidocaine using behavioural measures in rats. We then performed in vivo patch-clamp recording from spinal substantia gelatinosa (SG) neurons. Intravenous lidocaine had a dose-dependent analgesic effect on the withdrawal response to noxious mechanical stimuli. In the electrophysiological experiments, intravenous lidocaine inhibited the excitatory postsynaptic currents (EPSCs) evoked by noxious pinch stimuli. Intravenous lidocaine also decreased the frequency, but did not change the amplitude, of both spontaneous and miniature EPSCs. However, it did not affect inhibitory postsynaptic currents. Furthermore, intravenous lidocaine induced outward currents in SG neurons. Intravenous lidocaine inhibits glutamate release from presynaptic terminals in spinal SG neurons. Concomitantly, it hyperpolarizes postsynaptic neurons by shifting the membrane potential. This decrease in the excitability of spinal dorsal horn neurons may be a possible mechanism for the analgesic action of intravenous lidocaine in acute pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep26253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870564PMC
May 2016

Stimulation of dopamine D2-like receptors in the lumbosacral defaecation centre causes propulsive colorectal contractions in rats.

J Physiol 2016 08 28;594(15):4339-50. Epub 2016 Apr 28.

Department of Basic Veterinary Science, Laboratory of Physiology, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.

Key Points: The pathophysiological roles of the CNS in bowel dysfunction in patients with irritable bowel syndrome and Parkinson's disease remain obscure. In the present study, we demonstrate that dopamine in the lumbosacral defaecation centre causes strong propulsive motility of the colorectum. The effect of dopamine is a result of activation of sacral parasympathetic preganglionic neurons via D2-like dopamine receptors. Considering that dopamine is a neurotransmitter of descending pain inhibitory pathways, our results highlight the novel concept that descending pain inhibitory pathways control not only pain, but also the defaecation reflex. In addition, severe constipation in patients with Parkinson's disease can be explained by reduced parasympathetic outflow as a result of a loss of the effect of dopaminergic neurons.

Abstract: We have recently demonstrated that intrathecally injected noradrenaline caused propulsive contractions of the colorectum. We hypothesized that descending pain inhibitory pathways control not only pain, but also the defaecation reflex. Because dopamine is one of the major neurotransmitters of descending pain inhibitory pathways in the spinal cord, we examined the effects of the intrathecal application of dopamine to the spinal defaecation centre on colorectal motility. Colorectal intraluminal pressure and expelled volume were recorded in vivo in anaesthetized rats. Slice patch clamp and immunohistochemistry were used to confirm the existence of dopamine-sensitive neurons in the sacral parasympathetic nuclei. Intrathecal application of dopamine into the L6-S1 spinal cord, where the lumbosacral defaecation centre is located, caused propulsive contractions of the colorectum. Inactivation of spinal neurons using TTX blocked the effect of dopamine. Although thoracic spinal transection had no effect on the enhancement of colorectal motility by intrathecal dopamine, the severing of the pelvic nerves abolished the enhanced motility. Pharmacological experiments revealed that the effect of dopamine is mediated primarily by D2-like dopamine receptors. Neurons labelled with retrograde dye injected at the colorectum showed an inward current in response to dopamine in slice patch clamp recordings. Furthermore, immunohistochemical analysis revealed that neurons immunoreactive to choline acetyltransferase express D2-like dopamine receptors. Taken together, our findings demonstrate that dopamine activates sacral parasympathetic preganglionic neurons via D2-like dopamine receptors and causes propulsive motility of the colorectum in rats. The present study supports the hypothesis that descending pain inhibitory pathways regulate defaecation reflexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP272073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967751PMC
August 2016

Structure-function correlations of rat trigeminal primary neurons: Emphasis on club-like endings, a vibrissal mechanoreceptor.

Proc Jpn Acad Ser B Phys Biol Sci 2015 ;91(10):560-76

Department of Anatomy, Meiji University of Integrative Medicine.

This study focuses on the structure and function of the primary sensory neurons that innervate vibrissal follicles in the rat. Both the peripheral and central terminations, as well as their firing properties were identified using intracellular labelling and recording in trigeminal ganglia in vivo. Fifty-one labelled neurons terminating peripherally, as club-like, Merkel, lanceolate, reticular or spiny endings were identified by their morphology. All neurons responded robustly to air puff stimulation applied to the vibrissal skin. Neurons with club-like endings responded with the highest firing rates; their peripheral processes rarely branched between the cell body and their terminal tips. The central branches of these neurons displayed abundant collaterals terminating within all trigeminal nuclei. Analyses of three-dimensional reconstructions reveal a palisade arrangement of club-like endings bound to the ringwulst by collagen fibers. Our morphological findings suggest that neurons with club-like endings sense mechanical aspects related to the movement of the ringwulst and convey this information to all trigeminal nuclei in the brainstem.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2183/pjab.91.560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773582PMC
September 2016

Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons.

Proc Natl Acad Sci U S A 2015 Apr 6;112(16):5213-8. Epub 2015 Apr 6.

Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, Okazaki 444-8787, Japan; Department of Physiological Sciences, Graduate University for Advanced Studies, Okazaki 444-8787, Japan

The capsaicin receptor transient receptor potential cation channel vanilloid 1 (TRPV1) is activated by various noxious stimuli, and the stimuli are converted into electrical signals in primary sensory neurons. It is believed that cation influx through TRPV1 causes depolarization, leading to the activation of voltage-gated sodium channels, followed by the generation of action potential. Here we report that the capsaicin-evoked action potential could be induced by two components: a cation influx-mediated depolarization caused by TRPV1 activation and a subsequent anion efflux-mediated depolarization via activation of anoctamin 1 (ANO1), a calcium-activated chloride channel, resulting from the entry of calcium through TRPV1. The interaction between TRPV1 and ANO1 is based on their physical binding. Capsaicin activated the chloride currents in an extracellular calcium-dependent manner in HEK293T cells expressing TRPV1 and ANO1. Similarly, in mouse dorsal root ganglion neurons, capsaicin-activated inward currents were inhibited significantly by a specific ANO1 antagonist, T16Ainh-A01 (A01), in the presence of a high concentration of EGTA but not in the presence of BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid]. The generation of a capsaicin-evoked action potential also was inhibited by A01. Furthermore, pain-related behaviors in mice treated with capsaicin, but not with αβ-methylene ATP, were reduced significantly by the concomitant administration of A01. These results indicate that TRPV1-ANO1 interaction is a significant pain-enhancing mechanism in the peripheral nervous system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1421507112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413337PMC
April 2015
-->