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Activation of Interleukin-1beta receptor suppresses the voltage-gated potassium currents in the small-diameter trigeminal ganglion neurons following peripheral inflammation
S214
Abstracts
cell-type specific postnatal differentiation of excitatory and inhibitory postsynaptic current(EPSC and lPSC) patterns during the critical periods(P6–8). In the present study we reexamined the developmental rewiring in terms of intranuclear celllocation rather than mere cell-type. In dorsal subnuclei where small glutamatergic cells are predominant, EPSC frequency in each cell increased during development. In ventral regions where small GABAergic cells aggregate, EPSC frequency decreased while that of lPSCs increased. Geometric parameters such as cell location and the relative distance from other cells with specific type, could predict the matured wiring. Thus, the developmental spatial differentiation of excitability might underlie developmental rewiring of cNTS microcircuit necessary for functional maturation of autonomic homeostasis. doi:10.1016/j.neures.2009.09.1184
P3-d03 Projection of slow-conducting somatic afferents to the visceral representing region in the rat sensorimotor cortex Shin-ichi Ito Shimane University School of Medicine, Japan Vagus nerve stimulation evokes a response in the most rostral region of the sensrimotor cortex as well as in the insular cortex. In rats, the insular vagal region also receives input from primary somatic A-delta afferents over the entire body surface and this convergence appeared to occur in early stages of ascending pathways. This somatic input is likely to project to the vagal region in the sensorimotor cortex, as well. We examined this issue with evoked potentials methods. In anesthetized and artificially ventilated rats, a positive-negative potential was evoked in response to electrical stimulation regardless of the stimulating site (forepaws, hindpaws and tail), in almost the same region as the vagus evoked potential. Thresholds, as well as the peripheral conduction velocities measured at the tail, were almost the same as those of the insular potential. Thus, the visceral regions in the rat sensorimotor and insular cortices share the same somatic input, possibly containing thermosensory and nociceptive information. doi:10.1016/j.neures.2009.09.1185
P3-d04 Effect of anesthesia on blood oxygenation level-dependent signal changes in response to ingested L-glutamate in rats Tomokazu Tsurugizawa, Akira Uematsu, Hisayuki Uneyama, Kunio Torii Institute of Life Sciences, Ajinomoto Co., Inc., Japan It is important to investigate the effect of anesthesia on blood oxygenation leveldependent (BOLD) signals. Previously we have shown that ingested L-glutamate stimulates the gut, causing the activation in the forebrain regions in alpha-chloraloseanesthetized rats. However it has been unknown that the differences in the BOLD response between anesthetized and awake rats when a visceral nutrient signal arises. Here, we investigated the differences in BOLD signal changes after intragastric administration of L-glutamate, under three anesthesia conditions: awake, alphachloralose-anesthesia, and isoflurane-anesthesia. To measure the BOLD response in awake rats, we developed the training methods to make animals adapt to the MRI condition. We observed the significant BOLD signal increase in the prefrontal cortex and lateral hypothalamus only in awake rats following the intragastric infusion of Lglutamate. These results suggest that anesthetics could modulate the BOLD signals in rat functional MRI study for food intake. doi:10.1016/j.neures.2009.09.1186
P3-d05 Activation of Interleukin-1beta receptor suppresses the voltage-gated potassium currents in the small-diameter trigeminal ganglion neurons following peripheral inflammation Mamoru Takeda, Junnichi Kitagawa, Masayuku Takahashi, Shigeji Matsumoto Nippon Dental University, Japan Previously, the glial cytokine, interleukin-1beta (IL-1beta), potentiates the excitability of nociceptive trigeminal ganglion (TRG) neurons via membrane depolarization following peripheral inflammation. Perforated patch-clamp technique was used in the present study to show that the mechanism underlying the excitability of smalldiameter TRG neurons following inflammation is due to IL-1beta. IL-1beta at 1 nM suppressed total voltage-gated K+ currents in most TRG neurons under voltageclamp conditions in control and inflamed rats. IL-1beta significantly decreased the total, transient (IA) and sustained (IK) currents in FG-labeled small-diameter TRG neurons in both groups. The IL-1beta-induced suppression of TRG neuron excitability was abolished by co-administration of ILra, an IL-1beta receptor blocker. Our results provide evidence for the development of voltage-gated K+ channel open-
ers and IL-1beta antagonists as therapeutic agents for the treatment of trigeminal inflammatory hyperalgesia. doi:10.1016/j.neures.2009.09.1187
P3-d06 Activation of RET in uninjured primary sensory neurons contributes to the development of pain hypersensitivity after nerve injury Koichi Obata, Kan Miyoshi, Koichi Noguchi Hyogo College of Medicine, Japan There is compelling evidence indicating that not only injured primary afferents, but also their spared neighbors, show an alteration of excitability and gene expression and that these changes have functional roles in neuropathic pain. Artemin, a neuronal survival factor in the glial cell line-derived neurotrophic factor family, binds the glycosylphosphatidylinositol-anchored protein GFR␣3 and the receptor tyrosine kinase RET. However, the role of RET in neuropathic pain has not been explored. Here we report that the pharmacological blockade of RET in primary sensory neurons reversed neuropathic pain after nerve injury. Nerve injury increased the phosphorylation of RET in the uninjured dorsal root ganglion (DRG). Intrathecal administration of anti-GFR␣3 suppressed injury-induced heat hyperalgesia and decreased the phosphorylation of RET and p38 mitogen-activated protein kinase, and the induction of TRPV1 in undamaged DRG neurons. Our results show that augmentation of GFR␣3/RET signaling in uninjured sensory neurons has a crucial role in the pathogenesis of neuropathic pain. doi:10.1016/j.neures.2009.09.1188
P3-d07 Interleukin-1 converting enzyme (ICE) upregulation in spinal glial cells contributes to tactile allodynia after nerve injury Kan Miyoshi, Koichi Obata, Koichi Noguchi Hyogo College of Medicine, Japan Interleukin-1 converting enzyme (ICE) is a novel cysteine protease that cleaves the Interleukin-1 (IL-1) and IL-18. Recently, we have showed that the IL-18-mediated microglia/astrocyte interaction enhances neuropathic pain processing after nerve injury. We now show that ICE induced in spinal dorsal horn is crucial for tactile allodynia after peripheral nerve injury. Nerve injury induced a striking increase in ICE expression in the ipsilateral dorsal horn, and ICE was upregulated in hyperactive microglia. Functional inhibition of ICE signaling pathways suppressed nerve injury-induced tactile allodynia, and decreased the level of IL-18 in spinal cord. Our results indicate that ICE upregulation in spinal microglia has a substantial role in the generation of tactile allodynia through the IL-18 pathway. Thus, blocking ICE/IL-18 signaling in spinal glial cells might provide a fruitful strategy for treating neuropathic pain. doi:10.1016/j.neures.2009.09.1189
P3-d08 Induction of P2 receptors in the spinal microglia following peripheral nerve injury Kimiko Kobayashi, Hiroki Yamanaka, Masamichi Okubo, Koichi Noguchi Dept Anat and Neurosci, Hyogo College of Medicine, Japan The ATP purinergic (P2) receptor family has been divided into P2X ionotropic receptors (P2X1–7) and P2Y metabotropic G protein-coupled receptors (P2Y1, 2, 4, 6, 12, 13, 14). Recent findings suggest the some P2 receptors in the spinal cord may be involved in the pathogenesis of abnormal pain. In this study, we examined the changes in expression of P2 receptors in the rat spinal cord of neuropathic pain model. Using spared nerve injury (SNI) model rat, we investigated the expression of P2 receptors mRNA in spinal cord. RT-PCR revealed that P2X7, P2Y6, 13, 14 receptors mRNA showed the increase following SNI and peaked at 3 day after injury. Next, we examined their cellular distribution after SNI in the spinal cord using in situ hybridization histochemistry. Following SNI, P2X7, P2Y6, 13, 14 mRNA increased strikingly in microglia in the ipsilateral dorsal horn. Our data suggest that the ATP and other nucleotides may modulate the activated microglia, which show the upregulation of P2 receptors following nerve injury. doi:10.1016/j.neures.2009.09.1190
P3-d09 Platelet-activating factor biosynthesis in spinal cord contributes to neuropathic pain following peripheral nerve injury Masamichi Okubo, Hiroki Yamanaka, Kimiko Kobayashi, Koichi Noguchi Department Anatomy and Neuroscience, Hyogo College of Medicine, Japan
Abstracts
cell-type specific postnatal differentiation of excitatory and inhibitory postsynaptic current(EPSC and lPSC) patterns during the critical periods(P6–8). In the present study we reexamined the developmental rewiring in terms of intranuclear celllocation rather than mere cell-type. In dorsal subnuclei where small glutamatergic cells are predominant, EPSC frequency in each cell increased during development. In ventral regions where small GABAergic cells aggregate, EPSC frequency decreased while that of lPSCs increased. Geometric parameters such as cell location and the relative distance from other cells with specific type, could predict the matured wiring. Thus, the developmental spatial differentiation of excitability might underlie developmental rewiring of cNTS microcircuit necessary for functional maturation of autonomic homeostasis. doi:10.1016/j.neures.2009.09.1184
P3-d03 Projection of slow-conducting somatic afferents to the visceral representing region in the rat sensorimotor cortex Shin-ichi Ito Shimane University School of Medicine, Japan Vagus nerve stimulation evokes a response in the most rostral region of the sensrimotor cortex as well as in the insular cortex. In rats, the insular vagal region also receives input from primary somatic A-delta afferents over the entire body surface and this convergence appeared to occur in early stages of ascending pathways. This somatic input is likely to project to the vagal region in the sensorimotor cortex, as well. We examined this issue with evoked potentials methods. In anesthetized and artificially ventilated rats, a positive-negative potential was evoked in response to electrical stimulation regardless of the stimulating site (forepaws, hindpaws and tail), in almost the same region as the vagus evoked potential. Thresholds, as well as the peripheral conduction velocities measured at the tail, were almost the same as those of the insular potential. Thus, the visceral regions in the rat sensorimotor and insular cortices share the same somatic input, possibly containing thermosensory and nociceptive information. doi:10.1016/j.neures.2009.09.1185
P3-d04 Effect of anesthesia on blood oxygenation level-dependent signal changes in response to ingested L-glutamate in rats Tomokazu Tsurugizawa, Akira Uematsu, Hisayuki Uneyama, Kunio Torii Institute of Life Sciences, Ajinomoto Co., Inc., Japan It is important to investigate the effect of anesthesia on blood oxygenation leveldependent (BOLD) signals. Previously we have shown that ingested L-glutamate stimulates the gut, causing the activation in the forebrain regions in alpha-chloraloseanesthetized rats. However it has been unknown that the differences in the BOLD response between anesthetized and awake rats when a visceral nutrient signal arises. Here, we investigated the differences in BOLD signal changes after intragastric administration of L-glutamate, under three anesthesia conditions: awake, alphachloralose-anesthesia, and isoflurane-anesthesia. To measure the BOLD response in awake rats, we developed the training methods to make animals adapt to the MRI condition. We observed the significant BOLD signal increase in the prefrontal cortex and lateral hypothalamus only in awake rats following the intragastric infusion of Lglutamate. These results suggest that anesthetics could modulate the BOLD signals in rat functional MRI study for food intake. doi:10.1016/j.neures.2009.09.1186
P3-d05 Activation of Interleukin-1beta receptor suppresses the voltage-gated potassium currents in the small-diameter trigeminal ganglion neurons following peripheral inflammation Mamoru Takeda, Junnichi Kitagawa, Masayuku Takahashi, Shigeji Matsumoto Nippon Dental University, Japan Previously, the glial cytokine, interleukin-1beta (IL-1beta), potentiates the excitability of nociceptive trigeminal ganglion (TRG) neurons via membrane depolarization following peripheral inflammation. Perforated patch-clamp technique was used in the present study to show that the mechanism underlying the excitability of smalldiameter TRG neurons following inflammation is due to IL-1beta. IL-1beta at 1 nM suppressed total voltage-gated K+ currents in most TRG neurons under voltageclamp conditions in control and inflamed rats. IL-1beta significantly decreased the total, transient (IA) and sustained (IK) currents in FG-labeled small-diameter TRG neurons in both groups. The IL-1beta-induced suppression of TRG neuron excitability was abolished by co-administration of ILra, an IL-1beta receptor blocker. Our results provide evidence for the development of voltage-gated K+ channel open-
ers and IL-1beta antagonists as therapeutic agents for the treatment of trigeminal inflammatory hyperalgesia. doi:10.1016/j.neures.2009.09.1187
P3-d06 Activation of RET in uninjured primary sensory neurons contributes to the development of pain hypersensitivity after nerve injury Koichi Obata, Kan Miyoshi, Koichi Noguchi Hyogo College of Medicine, Japan There is compelling evidence indicating that not only injured primary afferents, but also their spared neighbors, show an alteration of excitability and gene expression and that these changes have functional roles in neuropathic pain. Artemin, a neuronal survival factor in the glial cell line-derived neurotrophic factor family, binds the glycosylphosphatidylinositol-anchored protein GFR␣3 and the receptor tyrosine kinase RET. However, the role of RET in neuropathic pain has not been explored. Here we report that the pharmacological blockade of RET in primary sensory neurons reversed neuropathic pain after nerve injury. Nerve injury increased the phosphorylation of RET in the uninjured dorsal root ganglion (DRG). Intrathecal administration of anti-GFR␣3 suppressed injury-induced heat hyperalgesia and decreased the phosphorylation of RET and p38 mitogen-activated protein kinase, and the induction of TRPV1 in undamaged DRG neurons. Our results show that augmentation of GFR␣3/RET signaling in uninjured sensory neurons has a crucial role in the pathogenesis of neuropathic pain. doi:10.1016/j.neures.2009.09.1188
P3-d07 Interleukin-1 converting enzyme (ICE) upregulation in spinal glial cells contributes to tactile allodynia after nerve injury Kan Miyoshi, Koichi Obata, Koichi Noguchi Hyogo College of Medicine, Japan Interleukin-1 converting enzyme (ICE) is a novel cysteine protease that cleaves the Interleukin-1 (IL-1) and IL-18. Recently, we have showed that the IL-18-mediated microglia/astrocyte interaction enhances neuropathic pain processing after nerve injury. We now show that ICE induced in spinal dorsal horn is crucial for tactile allodynia after peripheral nerve injury. Nerve injury induced a striking increase in ICE expression in the ipsilateral dorsal horn, and ICE was upregulated in hyperactive microglia. Functional inhibition of ICE signaling pathways suppressed nerve injury-induced tactile allodynia, and decreased the level of IL-18 in spinal cord. Our results indicate that ICE upregulation in spinal microglia has a substantial role in the generation of tactile allodynia through the IL-18 pathway. Thus, blocking ICE/IL-18 signaling in spinal glial cells might provide a fruitful strategy for treating neuropathic pain. doi:10.1016/j.neures.2009.09.1189
P3-d08 Induction of P2 receptors in the spinal microglia following peripheral nerve injury Kimiko Kobayashi, Hiroki Yamanaka, Masamichi Okubo, Koichi Noguchi Dept Anat and Neurosci, Hyogo College of Medicine, Japan The ATP purinergic (P2) receptor family has been divided into P2X ionotropic receptors (P2X1–7) and P2Y metabotropic G protein-coupled receptors (P2Y1, 2, 4, 6, 12, 13, 14). Recent findings suggest the some P2 receptors in the spinal cord may be involved in the pathogenesis of abnormal pain. In this study, we examined the changes in expression of P2 receptors in the rat spinal cord of neuropathic pain model. Using spared nerve injury (SNI) model rat, we investigated the expression of P2 receptors mRNA in spinal cord. RT-PCR revealed that P2X7, P2Y6, 13, 14 receptors mRNA showed the increase following SNI and peaked at 3 day after injury. Next, we examined their cellular distribution after SNI in the spinal cord using in situ hybridization histochemistry. Following SNI, P2X7, P2Y6, 13, 14 mRNA increased strikingly in microglia in the ipsilateral dorsal horn. Our data suggest that the ATP and other nucleotides may modulate the activated microglia, which show the upregulation of P2 receptors following nerve injury. doi:10.1016/j.neures.2009.09.1190
P3-d09 Platelet-activating factor biosynthesis in spinal cord contributes to neuropathic pain following peripheral nerve injury Masamichi Okubo, Hiroki Yamanaka, Kimiko Kobayashi, Koichi Noguchi Department Anatomy and Neuroscience, Hyogo College of Medicine, Japan