The Experts below are selected from a list of 30567 Experts worldwide ranked by ideXlab platform
Kazuhide Inoue - One of the best experts 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, 2008Co-Authors: Makoto Tsuda, Hikaru Ueno, Ayako Kataoka, Hidetoshi Tozakisaitoh, Kazuhide InoueAbstract: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, 2003Co-Authors: Makoto Tsuda, Shinichi Kohsaka, Akito Mizokoshi, Yukari Shigemotomogami, Schuichi Koizumi, Michael W. Salter, Kazuhide InoueAbstract: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, 2000Co-Authors: Makoto Tsuda, Schuichi Koizumi, Aya Kita, Yukari Shigemoto, Shinya Ueno, Kazuhide InoueAbstract:: 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 - One of the best experts on this subject based on the ideXlab platform.
-
altered c tactile processing in human dynamic tactile Allodynia
Pain, 2013Co-Authors: Jaquette Liljencrantz, Malin Bjornsdotter, India Morrison, Simon Bergstrand, Marta Ceko, David A Seminowicz, Jonathan Cole, Catherine M Bushnell, Hakan OlaussonAbstract: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 - One of the best experts 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, 2008Co-Authors: Makoto Tsuda, Hikaru Ueno, Ayako Kataoka, Hidetoshi Tozakisaitoh, Kazuhide InoueAbstract: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, 2003Co-Authors: Makoto Tsuda, Shinichi Kohsaka, Akito Mizokoshi, Yukari Shigemotomogami, Schuichi Koizumi, Michael W. Salter, Kazuhide InoueAbstract: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, 2000Co-Authors: Makoto Tsuda, Schuichi Koizumi, Aya Kita, Yukari Shigemoto, Shinya Ueno, Kazuhide InoueAbstract:: 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.
Simon Akerman - One of the best experts on this subject based on the ideXlab platform.
-
nitroglycerine triggers triptan responsive cranial Allodynia and trigeminal neuronal hypersensitivity
Brain, 2019Co-Authors: Simon Akerman, Nazia Karsan, Pyari Bose, Jan Hoffmann, Philip R HollandAbstract:: Cranial Allodynia associated with spontaneous migraine is reported as either responsive to triptan treatment or to be predictive of lack of triptan efficacy. These conflicting results suggest that a single mechanism mediating the underlying neurophysiology of migraine symptoms is unlikely. The lack of a translational approach to study cranial Allodynia reported in migraine patients is a limitation in dissecting potential mechanisms. Our objective was to study triptan-responsive cranial Allodynia in migraine patients, and to develop an approach to studying its neural basis in the laboratory. Using nitroglycerine to trigger migraine attacks, we investigated whether cranial Allodynia could be triggered experimentally, observing its response to treatment. Preclinically, we examined the cephalic response properties of central trigeminocervical neurons using extracellular recording techniques, determining changes to ongoing firing and somatosensory cranial-evoked sensitivity, in response to nitroglycerine followed by triptan treatment. Cranial Allodynia was triggered alongside migraine-like headache in nearly half of subjects. Those who reported cranial Allodynia accompanying their spontaneous migraine attacks were significantly more likely to have symptoms triggered than those that did not. Patients responded to treatment with aspirin or sumatriptan. Preclinically, nitroglycerine caused an increase in ongoing firing and hypersensitivity to intracranial-dural and extracranial-cutaneous (noxious and innocuous) somatosensory stimulation, reflecting signatures of central sensitization potentially mediating throbbing headache and cranial Allodynia. These responses were aborted by a triptan. These data suggest that nitroglycerine can be used as an effective and reliable method to trigger cranial Allodynia in subjects during evoked migraine, and the symptom is responsive to abortive triptan treatments. Preclinically, nitroglycerine activates the underlying neural mechanism of cephalic migraine symptoms, central sensitization, also predicting the clinical outcome to triptans. This supports a biological rationale that several mechanisms can mediate the underlying neurophysiology of migraine symptoms, with nitrergic-induced changes reflecting one that is relevant to spontaneous migraine in many migraineurs, whose symptoms of cranial Allodynia are responsive to triptan treatment. This approach translates directly to responses in animals and is therefore a relevant platform to study migraine pathophysiology, and for use in migraine drug discovery.
Tony L Yaksh - One of the best experts on this subject based on the ideXlab platform.
-
Toll-like receptor signaling regulates cisplatin-induced mechanical Allodynia in mice
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Hue Jung Park, Jennifer A. Stokes, Maripat Corr, Tony L YakshAbstract:Purpose Cisplatin-treated mice develop a persistent pain state and a condition wherein otherwise innocuous tactile stimuli evoke pain behavior, e.g., tactile Allodynia. The Allodynia is associated with an up-regulation of activation transcription factor 3 (ATF3) in the dorsal root ganglia (DRG), a factor, which is activated by Toll-like receptors (TLRs). Accordingly, we sought to examine the role of the TLR signaling cascade on Allodynia, weight, and changes in DRG ATF3 in cisplatin-treated mice. Methods Cisplatin (2.3 mg/kg/day × 6 injections every other day) or vehicle was administered to male wild-type (WT) C57BL/6, Tlr3 ^− / −, Tlr4 ^− / −, Myd88 ^− / −, Trif ^ lps2 and Myd88/Trif ^ lps2 mice. We examined Allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining. Results (1) WT cisplatin-treated mice showed tactile Allodynia from day 3 through day 30. (2) The Myd88/Trif ^ lps2 mice did not show Allodynia. (3) In Tlr3 ^− / − , Tlr4 ^− / −, and Myd88 ^− / − mice, withdrawal thresholds were elevated toward normal versus WT cisplatin-treated mice, but remained decreased as compared to vehicle mice. (4) In Trif ^ lps2 mice, cisplatin Allodynia showed a delayed onset, but persisted. (5) In Tlr3 ^−/−, Tlr4 ^− / − , Myd88 ^− / −, and Myd88/Trif ^ lps2 mice, the increase in DRG ATF3 was abolished. (6) Weight loss occurred during cisplatin administration, which was exacerbated in mutant as compared to WT mice. Conclusions Cisplatin evoked a persistent Allodynia and DRG ATF3 expression in WT mice, but these effects were reduced in mice with TLR signaling deficiency. TLR signaling may thus be involved in the mechanisms leading to the cisplatin polyneuropathy.
-
the effect of spinal gaba receptor agonists on tactile Allodynia in a surgically induced neuropathic pain model in the rat
Pain, 1997Co-Authors: Jai Hyun Hwang, Tony L YakshAbstract:Abstract This study evaluated the effects of spinal gamma-aminobutyric acid (GABA) receptor agonists on the tactile Allodynia observed in rats with ligation of the L5/L6 nerve roots (Chung model) and chronic lumbar intrathecal catheters. In these rats, the spinal injection of the GABA b agonist baclofen (BAC; 0.03–0.3 μg) and GABA a agonist muscimol (MUS; 0.1–1.0 μg) resulted in a dose-dependent antagonism of the Allodynia at doses which had no detectable effect upon motor function. Intrathecal injection of the GABA b antagonist CGP 35348 (CGP; 30 μg) or the GABA a antagonist bicuculline (BIC; 0.3 μg) prior to injection of each GABA receptor agonist had little effect upon normal or tactile allodynic thresholds, but significantly reversed the anti-allodynic effects produced by the respective receptor agonists. The antagonistic effects were limited to the agonist of the respective receptor. These observations indicate that spinal GABA a and GABA b receptors modulate spinal systems activated by low threshold mechanoreceptors which mediate the Allodynia observed following peripheral nerve injury.