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Allodynia

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Kazuhide Inoue – 1st expert on this subject based on the ideXlab platform

  • activation of dorsal horn microglia contributes to diabetes induced tactile Allodynia via extracellular signal regulated protein kinase signaling
    Glia, 2008
    Co-Authors: Makoto Tsuda, Hikaru Ueno, Ayako Kataoka, Hidetoshi Tozakisaitoh, Kazuhide Inoue

    Abstract:

    Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile Allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile Allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile Allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile Allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile Allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile Allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of Allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile Allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile Allodynia. © 2008 Wiley-Liss, Inc.

  • p2x4 receptors induced in spinal microglia gate tactile Allodynia after nerve injury
    Nature, 2003
    Co-Authors: Makoto Tsuda, Yukari Shigemotomogami, Schuichi Koizumi, Akito Mizokoshi, Shinichi Kohsaka, Michael W. Salter, Kazuhide Inoue

    Abstract:

    Pain after nerve damage is an expression of pathological operation of the nervous system1,2, one hallmark of which is tactile Allodynia—pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs)3,4,5,6,7, a subtype of ionotropic ATP receptor8, reversed tactile Allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile Allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile Allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile Allodynia after nerve injury and is sufficient to produce tactile Allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.

  • mechanical Allodynia caused by intraplantar injection of p2x receptor agonist in rats involvement of heteromeric p2x2 3 receptor signaling in capsaicin insensitive primary afferent neurons
    The Journal of Neuroscience, 2000
    Co-Authors: Makoto Tsuda, Schuichi Koizumi, Aya Kita, Yukari Shigemoto, Shinya Ueno, Kazuhide Inoue

    Abstract:

    : Extracellular ATP has been known to activate sensory neurons via the ATP-gated ion channels P2X receptors, indicating that the P2X receptors may play a role in signal transduction of pain from the periphery to the spinal cord in vivo. Here, we found a novel nociceptive response induced by ATP, mechanical Allodynia (hypersensitivity to innocuous mechanical stimulus). Injection of alpha,beta-methylene ATP (alpha(beta)meATP), an agonist to P2X receptor, into plantar surface in rats produced the mechanical Allodynia along with previously described nocifensive behavior and thermal hyperalgesia. This allodynic response was blocked by pretreatment with the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate. Interestingly, only the mechanical Allodynia evoked by alpha(beta)meATP selectively remained in neonatal capsaicin-treated adult rats that had selectively lost the capsaicin-sensitive neurons. ATP has been shown to produce two distinguishable electrophysiological responses (inward currents with rapid and slow desensitization) in dorsal root ganglion (DRG) neurons. In the present electrophysiological experiment, the percentage of DRG neurons that responded to alpha(beta)meATP with slow desensitizing inward current remained constant in capsaicin-treated rats, whereas the percentage that responded with rapid desensitizing current dramatically decreased. Taken together with our previous finding that the alpha(beta)meATP-activated slow desensitizing current in DRG neurons is mediated by heteromeric P2X2/3 (P2X2 and P2X3) receptors, it is hypothesized that activation of heteromeric P2X2/3 receptors in peripheral terminals of capsaicin-insensitive primary afferent fibers leads to the induction of mechanical Allodynia.

Hakan Olausson – 2nd expert on this subject based on the ideXlab platform

  • altered c tactile processing in human dynamic tactile Allodynia
    Pain, 2013
    Co-Authors: Jaquette Liljencrantz, Hakan Olausson, Malin Bjornsdotter, India Morrison, Simon Bergstrand, Marta Ceko, David A Seminowicz, Jonathan Cole, Catherine M Bushnell

    Abstract:

    Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile Allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for Allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile Allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile Allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.

Makoto Tsuda – 3rd expert on this subject based on the ideXlab platform

  • activation of dorsal horn microglia contributes to diabetes induced tactile Allodynia via extracellular signal regulated protein kinase signaling
    Glia, 2008
    Co-Authors: Makoto Tsuda, Hikaru Ueno, Ayako Kataoka, Hidetoshi Tozakisaitoh, Kazuhide Inoue

    Abstract:

    Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile Allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile Allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile Allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile Allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile Allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile Allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of Allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile Allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile Allodynia. © 2008 Wiley-Liss, Inc.

  • p2x4 receptors induced in spinal microglia gate tactile Allodynia after nerve injury
    Nature, 2003
    Co-Authors: Makoto Tsuda, Yukari Shigemotomogami, Schuichi Koizumi, Akito Mizokoshi, Shinichi Kohsaka, Michael W. Salter, Kazuhide Inoue

    Abstract:

    Pain after nerve damage is an expression of pathological operation of the nervous system1,2, one hallmark of which is tactile Allodynia—pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs)3,4,5,6,7, a subtype of ionotropic ATP receptor8, reversed tactile Allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile Allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile Allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile Allodynia after nerve injury and is sufficient to produce tactile Allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.

  • mechanical Allodynia caused by intraplantar injection of p2x receptor agonist in rats involvement of heteromeric p2x2 3 receptor signaling in capsaicin insensitive primary afferent neurons
    The Journal of Neuroscience, 2000
    Co-Authors: Makoto Tsuda, Schuichi Koizumi, Aya Kita, Yukari Shigemoto, Shinya Ueno, Kazuhide Inoue

    Abstract:

    : Extracellular ATP has been known to activate sensory neurons via the ATP-gated ion channels P2X receptors, indicating that the P2X receptors may play a role in signal transduction of pain from the periphery to the spinal cord in vivo. Here, we found a novel nociceptive response induced by ATP, mechanical Allodynia (hypersensitivity to innocuous mechanical stimulus). Injection of alpha,beta-methylene ATP (alpha(beta)meATP), an agonist to P2X receptor, into plantar surface in rats produced the mechanical Allodynia along with previously described nocifensive behavior and thermal hyperalgesia. This allodynic response was blocked by pretreatment with the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate. Interestingly, only the mechanical Allodynia evoked by alpha(beta)meATP selectively remained in neonatal capsaicin-treated adult rats that had selectively lost the capsaicin-sensitive neurons. ATP has been shown to produce two distinguishable electrophysiological responses (inward currents with rapid and slow desensitization) in dorsal root ganglion (DRG) neurons. In the present electrophysiological experiment, the percentage of DRG neurons that responded to alpha(beta)meATP with slow desensitizing inward current remained constant in capsaicin-treated rats, whereas the percentage that responded with rapid desensitizing current dramatically decreased. Taken together with our previous finding that the alpha(beta)meATP-activated slow desensitizing current in DRG neurons is mediated by heteromeric P2X2/3 (P2X2 and P2X3) receptors, it is hypothesized that activation of heteromeric P2X2/3 receptors in peripheral terminals of capsaicin-insensitive primary afferent fibers leads to the induction of mechanical Allodynia.