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Tony L Yaksh - One of the best experts on this subject based on the ideXlab platform.
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The effects of intraplantar and intrathecal botulinum toxin type B on Tactile Allodynia in mono and polyneuropathy in the mouse.
Anesthesia and analgesia, 2015Co-Authors: Hue Jung Park, Marc J. Marino, Eric S. Rondon, Tony L YakshAbstract:BACKGROUND:Mononeuropathies (MNs: nerve ligation) and polyneuropathies (PNs: cisplatin) produce unilateral and bilateral Tactile Allodynia, respectively. We examined the effects of intraplantar (IPLT) and intrathecal (IT) botulinum toxin B (BoNT-B) on this Allodynia.METHODS:Mice (male c57Bl/6) were
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Transient Tactile Allodynia following intrathecal puncture in mouse: Contributions of Toll-like receptor signaling
Neuroscience letters, 2011Co-Authors: Jennifer A. Stokes, Maripat Corr, Tony L YakshAbstract:Studies of spinal drug action in mice often involve percutaneous intrathecal drug administration delivered in a lightly anesthetized animal. A successful lumbar intrathecal (IT) needle stick of a lightly anesthetized (isoflurane) mouse evokes a tail flick, which is an indication of local spinal nerve stimulation. Immediately upon arousal, a hind paw Tactile Allodynia, as measured with von Frey hairs (pre 1.55±0.11 g vs. injected 0.66±0.08 g) lasts 3-4 h. In a similarly anesthetized mouse without the needle stick, a 1-h Allodynia was noted. In studies on spinal Toll-like receptor (TLR) signaling, we observed that following intrathecal puncture and mechanical stimulation of the nerve roots mice deficient in TLR down-stream signaling (Myd88(-/-)/Trif(lps2)), displayed only the transient (1-h) Allodynia otherwise observed following isoflurane alone. These data suggest that the extended period of hyperalgesia observed with needle penetration of the dura and mechanical stimulation of the nerve roots requires signaling through the MyD88/TRIF pathways and supports the intrinsic role of Toll-like receptors in the Allodynia secondary to the minor nerve activation occurring during the intradural puncture.
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spinal and peripheral μ opioids and the development of secondary Tactile Allodynia after thermal injury
Anesthesia & Analgesia, 2002Co-Authors: Natsuko Nozakitaguchi, Tony L YakshAbstract:Local thermal injury to the paw leads to an increased sensitivity to a noxious stimulus applied to the site (primary thermal hyperalgesia) and an increased sensitivity to Tactile stimuli in skin sites adjacent to the primary injury (secondary Tactile Allodynia; 2°TA). We sought to define the peripheral and spinal actions of opioids in regulating 2°TA. First, a mild thermal injury was induced on one heel, producing 2°TA. This 2°TA was blocked by pretreatment, but not posttreatment, with a topical -opioid agonist, loperamide (1.7%–5%). Second, 2°TA was blocked by intrathecal morphine (0.1–10 g) pre- and postinjury. 2°TA reappeared when systemic naloxone was given before, but not after, injury in intrathecal morphinepretreated rats. Intrathecal remifentanil, a short-lasting -opioid agonist, infused periinjury (3 g/min), did not block subsequent primary thermal hyperalgesia, but it produced a dose-dependent (0.3–3 g/min) abolition of 2°TA. Local tissue injury leads to 2°TA by the activation of opiate-sensitive afferents and the initiation of a cascade that persists in the absence of that initiating injuryinduced stimulus. (Anesth Analg 2002;94:968 –74)
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Pharmacology of Spinal Glutamatergic Receptors in Post–Thermal Injury–evoked Tactile Allodynia and Thermal Hyperalgesia
Anesthesiology, 2002Co-Authors: Natsuko Nozaki-taguchi, Tony L YakshAbstract:BACKGROUND After a focal thermal injury to the heel of a rat, thermal hyperalgesia appears at the injury site (primary thermal hyperalgesia), and Tactile Allodynia appears at the off-injury site (secondary Tactile Allodynia). The pharmacology of spinal glutamatergic receptors in the initiation and maintenance of secondary Tactile Allodynia was examined. METHODS In rats prepared with chronic intrathecal catheters, the heel of one hind paw was exposed to a 52 degrees C surface for 45 s, resulting in a local erythema without blistering. Intrathecal N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801, AP5) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptor antagonists (CNQX, NBQX, NS257, etc.) were administered either before (pretreatment) or after (posttreatment) the induction of the injury. Tactile withdrawal thresholds and thermal paw withdrawal latencies were assessed. RESULTS Pretreatment and posttreatment with AMPA-KA antagonists produced a dose-dependent blockade of secondary Tactile Allodynia. However, NMDA antagonists, in doses that effectively block other models of facilitated states, showed little or no effect. Primary thermal hyperalgesia was blocked only by high-dose AMPA-KA antagonists. CONCLUSION Spinal AMPA-KA receptors play a major role in the initiation of secondary Tactile Allodynia induced by focal thermal injury. In contrast, spinal NMDA receptors play only a minimal role.
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pharmacology of spinal glutamatergic receptors in post thermal injury evoked Tactile Allodynia and thermal hyperalgesia
Anesthesiology, 2002Co-Authors: Natsuko Nozakitaguchi, Tony L YakshAbstract:BACKGROUND After a focal thermal injury to the heel of a rat, thermal hyperalgesia appears at the injury site (primary thermal hyperalgesia), and Tactile Allodynia appears at the off-injury site (secondary Tactile Allodynia). The pharmacology of spinal glutamatergic receptors in the initiation and maintenance of secondary Tactile Allodynia was examined. METHODS In rats prepared with chronic intrathecal catheters, the heel of one hind paw was exposed to a 52 degrees C surface for 45 s, resulting in a local erythema without blistering. Intrathecal N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801, AP5) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptor antagonists (CNQX, NBQX, NS257, etc.) were administered either before (pretreatment) or after (posttreatment) the induction of the injury. Tactile withdrawal thresholds and thermal paw withdrawal latencies were assessed. RESULTS Pretreatment and posttreatment with AMPA-KA antagonists produced a dose-dependent blockade of secondary Tactile Allodynia. However, NMDA antagonists, in doses that effectively block other models of facilitated states, showed little or no effect. Primary thermal hyperalgesia was blocked only by high-dose AMPA-KA antagonists. CONCLUSION Spinal AMPA-KA receptors play a major role in the initiation of secondary Tactile Allodynia induced by focal thermal injury. In contrast, spinal NMDA receptors play only a minimal role.
Kazuhide Inoue - One of the best experts on this subject based on the ideXlab platform.
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Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and Tactile Allodynia in a rodent model of neuropathic pain.
PloS one, 2010Co-Authors: Shigeo Hasegawa, Makoto Tsuda, Yuta Kohro, Miho Shiratori, Satoshi Ishii, Takao Shimizu, Kazuhide InoueAbstract:BACKGROUND Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A(2) (cPLA(2)) in injured dorsal root ganglion (DRG) neurons that contribute to Tactile Allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA(2) activation to produce Tactile Allodynia remain to be determined. PRINCIPAL FINDINGS Here we provide evidence that platelet-activating factor (PAF) is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs) reduced the development and expression of Tactile Allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced Tactile Allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naive rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFalpha and IL-1beta, both of which were inhibited by pretreatment with a PAFR antagonist. CONCLUSIONS Our results indicate that the PAF/PAFR system has an important role in production of TNFalpha and IL-1beta in the DRG and Tactile Allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.
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Intrathecal delivery of PDGF produces Tactile Allodynia through its receptors in spinal microglia
Molecular pain, 2009Co-Authors: Junya Masuda, Hidetoshi Tozaki-saitoh, Makoto Tsuda, Kazuhide InoueAbstract:Neuropathic pain is a debilitating pain condition that occurs after nerve damage. Such pain is considered to be a reflection of the aberrant excitability of dorsal horn neurons. Emerging lines of evidence indicate that spinal microglia play a crucial role in neuronal excitability and the pathogenesis of neuropathic pain, but the mechanisms underlying neuron-microglia communications in the dorsal horn remain to be fully elucidated. A recent study has demonstrated that platelet-derived growth factor (PDGF) expressed in dorsal horn neurons contributes to neuropathic pain after nerve injury, yet how PDGF produces pain hypersensitivity remains unknown. Here we report an involvement of spinal microglia in PDGF-induced Tactile Allodynia. A single intrathecal delivery of PDGF B-chain homodimer (PDGF-BB) to naive rats produced a robust and long-lasting decrease in paw withdrawal threshold in a dose-dependent manner. Following PDGF administration, the immunofluorescence for phosphorylated PDGF β-receptor (p-PDGFRβ), an activated form, was markedly increased in the spinal dorsal horn. Interestingly, almost all p-PDGFRβ-positive cells were double-labeled with an antibody for the microglia marker OX-42, but not with antibodies for other markers of neurons, astrocytes and oligodendrocytes. PDGF-stimulated microglia in vivo transformed into a modest activated state in terms of their cell number and morphology. Furthermore, PDGF-BB-induced Tactile Allodynia was prevented by a daily intrathecal administration of minocycline, which is known to inhibit microglia activation. Moreover, in rats with an injury to the fifth lumbar spinal nerve (an animal model of neuropathic pain), the immunofluorescence for p-PDGFRβ was markedly enhanced exclusively in microglia in the ipsilateral dorsal horn. Together, our findings suggest that spinal microglia critically contribute to PDGF-induced Tactile Allodynia, and it is also assumed that microglial PDGF signaling may have a role in the pathogenesis of neuropathic pain.
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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, Hidetoshi Tozakisaitoh, Ayako Kataoka, 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.
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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, Hidetoshi Tozakisaitoh, Ayako Kataoka, 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.
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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 Tozaki-saitoh, 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.
Makoto Tsuda - One of the best experts on this subject based on the ideXlab platform.
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Interferon regulatory factor 8 expressed in microglia contributes to Tactile Allodynia induced by repeated cold stress in rodents
Journal of pharmacological sciences, 2014Co-Authors: Takanori Akagi, Hidetoshi Tozaki-saitoh, Yuta Matsumura, Masaya Yasui, Emiko Minami, Hidemasa Inoue, Takahiro Masuda, Tomohiko Tamura, Kazue Mizumura, Makoto TsudaAbstract:We investigated the role of interferon regulatory factor 8 (IRF8) in a model of chronic pain in which repeated cold stress (RCS) exposure produces Tactile Allodynia. RCS exposure produced a decrease in paw withdrawal threshold (PWT) to mechanical stimulation. Spinal microglia of RCS-exposed mice were morphologically activated. Expression of IRF8 was significantly increased in the spinal cord of RCS-exposed mice and was localized in microglia. IRF8-knockout mice failed to show the RCS-induced decrease in PWT. Thus, RCS exposure activates spinal microglia and upregulation of IRF8 in these cells is involved in the development of Tactile Allodynia after RCS exposure.
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Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and Tactile Allodynia in a rodent model of neuropathic pain.
PloS one, 2010Co-Authors: Shigeo Hasegawa, Makoto Tsuda, Yuta Kohro, Miho Shiratori, Satoshi Ishii, Takao Shimizu, Kazuhide InoueAbstract:BACKGROUND Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A(2) (cPLA(2)) in injured dorsal root ganglion (DRG) neurons that contribute to Tactile Allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA(2) activation to produce Tactile Allodynia remain to be determined. PRINCIPAL FINDINGS Here we provide evidence that platelet-activating factor (PAF) is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs) reduced the development and expression of Tactile Allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced Tactile Allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naive rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFalpha and IL-1beta, both of which were inhibited by pretreatment with a PAFR antagonist. CONCLUSIONS Our results indicate that the PAF/PAFR system has an important role in production of TNFalpha and IL-1beta in the DRG and Tactile Allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.
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Intrathecal delivery of PDGF produces Tactile Allodynia through its receptors in spinal microglia
Molecular pain, 2009Co-Authors: Junya Masuda, Hidetoshi Tozaki-saitoh, Makoto Tsuda, Kazuhide InoueAbstract:Neuropathic pain is a debilitating pain condition that occurs after nerve damage. Such pain is considered to be a reflection of the aberrant excitability of dorsal horn neurons. Emerging lines of evidence indicate that spinal microglia play a crucial role in neuronal excitability and the pathogenesis of neuropathic pain, but the mechanisms underlying neuron-microglia communications in the dorsal horn remain to be fully elucidated. A recent study has demonstrated that platelet-derived growth factor (PDGF) expressed in dorsal horn neurons contributes to neuropathic pain after nerve injury, yet how PDGF produces pain hypersensitivity remains unknown. Here we report an involvement of spinal microglia in PDGF-induced Tactile Allodynia. A single intrathecal delivery of PDGF B-chain homodimer (PDGF-BB) to naive rats produced a robust and long-lasting decrease in paw withdrawal threshold in a dose-dependent manner. Following PDGF administration, the immunofluorescence for phosphorylated PDGF β-receptor (p-PDGFRβ), an activated form, was markedly increased in the spinal dorsal horn. Interestingly, almost all p-PDGFRβ-positive cells were double-labeled with an antibody for the microglia marker OX-42, but not with antibodies for other markers of neurons, astrocytes and oligodendrocytes. PDGF-stimulated microglia in vivo transformed into a modest activated state in terms of their cell number and morphology. Furthermore, PDGF-BB-induced Tactile Allodynia was prevented by a daily intrathecal administration of minocycline, which is known to inhibit microglia activation. Moreover, in rats with an injury to the fifth lumbar spinal nerve (an animal model of neuropathic pain), the immunofluorescence for p-PDGFRβ was markedly enhanced exclusively in microglia in the ipsilateral dorsal horn. Together, our findings suggest that spinal microglia critically contribute to PDGF-induced Tactile Allodynia, and it is also assumed that microglial PDGF signaling may have a role in the pathogenesis of neuropathic pain.
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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, Hidetoshi Tozakisaitoh, Ayako Kataoka, 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.
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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, Hidetoshi Tozakisaitoh, Ayako Kataoka, 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.
Vinicio Granados-soto - One of the best experts on this subject based on the ideXlab platform.
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Supplementary figures -Supplemental material for ATF2, but not ATF3, participates in the maintenance of nerve injury-induced Tactile Allodynia and thermal hyperalgesia
2018Co-Authors: Ana B Salinas-abarca, Héctor I Rocha-gonzález, Jorge E. Torres-lópez, Isabel Velazquez-lagunas, Úrzula Franco-enzástiga, Vinicio Granados-sotoAbstract:Supplemental material, Supplementary figures for ATF2, but not ATF3, participates in the maintenance of nerve injury-induced Tactile Allodynia and thermal hyperalgesia by Ana B Salinas-Abarca, Isabel Velazquez-Lagunas, Úrzula Franco-Enzástiga, Jorge E Torres-López, Héctor I Rocha-González and Vinicio Granados-Soto in Molecular Pain
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Fosinopril Prevents the Development of Tactile Allodynia in a Streptozotocin-Induced Diabetic Rat Model
Drug development research, 2015Co-Authors: Claudia I Araiza-saldaña, Héctor I Rocha-gonzález, Gabriela Castañeda-corral, Erick Fabián Pedraza-priego, Jorge E. Torres-lópez, Enrique Hong-chong, Vinicio Granados-sotoAbstract:The aim of this study was to evaluate fosinopril-induced changes in hemodynamic parameters and Tactile Allodynia in a rat model of diabetes. Diabetes was induced by streptozotocin (STZ; 50 mg/kg, i.p.) in male Wistar rats. STZ produced hyperglycemia, weight loss, polydipsia, polyphagia, and polyuria as well as long-term arterial hypotension, bradycardia, and Tactile Allodynia at 10-12 weeks. Daily administration of the angiotensin converting enzyme inhibitor, fosinopril (25 mg/kg, p.o., for 11 weeks) partially reduced the loss of body weight, decreased hyperglycemia, and systolic blood pressure in diabetic rats. Likewise, systemic administration of fosinopril prevented the development and maintenance of Tactile Allodynia in STZ-induced diabetic rats. These data suggest that fosinopril may have a role in the pharmacotherapy of diabetic neuropathic pain.
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5-HT2B Receptor Antagonists Reduce Nerve Injury-Induced Tactile Allodynia and Expression of 5-HT2B Receptors.
Drug development research, 2015Co-Authors: Jorge Baruch Pineda-farias, Isabel Velazquez-lagunas, Paulino Barragán-iglesias, Claudia Cervantes-durán, Vinicio Granados-sotoAbstract:Preclinical Research This work was performed to assess the effects of intrathecal serotonin 2B (5-HT2B) receptor antagonists in rats with neuropathic pain. With RS-127445, its effect was also determined on 5-HT2B receptor expression. Neuropathic pain was induced by L5/L6 spinal nerve ligation. Western blotting was used to determine 5-HT2B receptor expression. Dose-response curves with the 5-HT2B receptor antagonists 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyridine (RS-127445, 1–100 nmol) and 1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-2,3,4,9-tetrahydro-6-methyl-1H-pyrido[3,4-b]indole hydrochloride (LY-266097, 1–100 nmol) were performed in rats. Tactile Allodynia of the left hind paw (ipsilateral) was assessed for 8 h after compound administration. Intrathecal injection of the 5-HT2B receptor antagonists RS-127445 and LY-266097 diminished spinal nerve ligation-induced Allodynia. In contrast, intrathecal injection of the 5-HT2 receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 10 nmol) did not modify Tactile Allodynia induced by nerve ligation. L5/L6 nerve ligation increased expression of the 5-HT2B receptors in the ipsilateral, but not contralateral, dorsal root ganglia. Furthermore, nerve injury also enhanced 5-HT2B receptor expression in the ipsilateral dorsal part of the spinal cord. Intrathecal treatment with RS-127445 (100 nmol) diminished spinal nerve injury-induced increased expression of 5-HT2B receptors in dorsal root ganglia and spinal cord. Our results imply that spinal 5-HT2B receptors are present on sites related to nociception and participate in neuropathic pain. © 2014 Wiley Periodicals, Inc Drug Dev Res 76 : 31–39, 2015
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Blockade of 5-HT7 receptors reduces Tactile Allodynia in the rat.
Pharmacology biochemistry and behavior, 2011Co-Authors: Evelyn Amaya-castellanos, Héctor I Rocha-gonzález, Gabriela Castañeda-corral, Jorge Baruch Pineda-farias, Guadalupe C. Vidal-cantú, Janet Murbartián, Vinicio Granados-sotoAbstract:Abstract This study assessed the role of systemic and spinal 5-HT 7 receptors on rats submitted to spinal nerve injury. In addition, the 5-HT 7 receptors level in dorsal root ganglion and spinal cord was also determined. Tactile Allodynia was induced by L5/L6 spinal nerve ligation. Systemic (0.01–10 mg/kg) or spinal (0.3–30 μg) administration of the selective 5-HT 7 receptor antagonist SB-269970 but not vehicle reduced in a dose-dependent manner established Tactile Allodynia. This effect was maintained for about 6 h. SB-269970 was more potent and effective by the spinal administration route than through systemic injection. Spinal nerve ligation reduced expression of 5-HT 7 receptors in the ipsilateral but not contralateral dorsal root ganglia. Moreover, 5-HT 7 receptor levels were lower in the ipsilateral dorsal spinal cord of neuropathic rats compared to naive and sham rats. No changes in the receptor levels were observed in the contralateral dorsal spinal cord and in both regions of the ventral spinal cord. Data suggest that spinal 5-HT 7 receptors play a pronociceptive role in neuropathic rats. Results also indicate that spinal nerve injury leads to a reduced 5-HT 7 receptors level in pain processing-related areas which may result from its nociceptive role in this model. Data suggest that selective 5-HT 7 receptor antagonists may function as analgesics in nerve injury pain states.
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Sildenafil and glyceryl trinitrate reduce Tactile Allodynia in streptozotocin-injected rats.
European journal of pharmacology, 2010Co-Authors: Claudia I Araiza-saldaña, Héctor I Rocha-gonzález, Mónica Ambriz-tututi, Gabriela Castañeda-corral, Nadia L Caram-salas, Enrique Hong, Vinicio Granados-sotoAbstract:The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term Tactile Allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1-5.6 mg/kg, i.p.) reduced Tactile Allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2mg/h) also reduced Tactile Allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce Tactile Allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of Tactile Allodynia in diabetic patients.
Sandra R. Chaplan - One of the best experts on this subject based on the ideXlab platform.
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Spinal pharmacology of Tactile Allodynia in diabetic rats
British Journal of Pharmacology, 1997Co-Authors: Nigel A. Calcutt, Sandra R. ChaplanAbstract:1 Rats develop Tactile Allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown. 2 Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether Tactile Allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing. 3 Dose-dependent inhibition of Tactile Allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the α2-adrenoceptor agonist dexmedetomidine, the μ-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX. 4 No effect on Tactile Allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle. 5 These data suggest that the Tactile Allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins.
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Spinal pharmacology of Tactile Allodynia in diabetic rats
British journal of pharmacology, 1997Co-Authors: Nigel A. Calcutt, Sandra R. ChaplanAbstract:1. Rats develop Tactile Allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown. 2. Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether Tactile Allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing. 3. Dose-dependent inhibition of Tactile Allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the alpha2-adrenoceptor agonist dexmedetomidine, the mu-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX. 4. No effect on Tactile Allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle. 5. These data suggest that the Tactile Allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins.
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Tactile Allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine.
Pain, 1996Co-Authors: Nigel A. Calcutt, Tony L Yaksh, Michael C Jorge, Sandra R. ChaplanAbstract:Rats developed Tactile Allodynia within days of the onset of diabetes and which persisted for up to 8 weeks. Allodynia was prevented by insulin therapy that maintained normoglycemia while established Allodynia was reversed by insulin therapy and normoglycemia of days but not hours duration. Tactile Allodynia persisted in diabetic rats that received enough insulin to maintain normal body and foot weights but remained hyperglycemic, whereas this therapy was sufficient to correct other nerve disorders in diabetic rats, including deficits of sensory and motor nerve conduction velocity, nerve blood flow and hyperalgesia during the formalin test. Treating diabetic rats with the aldose reductase inhibitor ICI 222155 did not prevent Tactile Allodynia. Tactile Allodynia was of similar magnitude in diabetic rats and nerve injured control rats and diabetes did not alter the magnitude or time course of nerve injury-induced Allodynia. Systemic lidocaine treatment alleviated Tactile Allodynia in nerve injured control rats and both sham-operated and nerve injured diabetic rats. The streptozotocin-diabetic rat develops Tactile Allodynia that appears to be related to prolonged periods of insulin deficiency or hyperglycemia and which is amenable to treatment with lidocaine. The model may be of use in investigating the efficacy of other potential therapeutic agents for treating painful diabetic neuropathy.
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prolonged alleviation of Tactile Allodynia by intravenous lidocaine in neuropathic rats
Anesthesiology, 1995Co-Authors: Sandra R. Chaplan, Flemming W Bach, Steven L Shafer, Tony L YakshAbstract:BackgroundLidocaine may be useful in the treatment of neuropathic pain states. The authors hypothesized that lidocaine would reduce Tactile Allodynia observed in a rat nerve injury model. In an effort to determine the site of drug action, effects after intravenous, intrathecal, and regional administ
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role of voltage dependent calcium channel subtypes in experimental Tactile Allodynia
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Sandra R. Chaplan, J W Pogrel, Tony L YakshAbstract:Peripheral nerve lesions can result in exaggerated pain responses to low intensity mechanical stimuli (Tactile Allodynia). In the present work, the pharmacology of voltage-dependent calcium channels (VDCCs) involved in the transmission of neuropathic pain was characterized by examining the effects of antagonists specific to the N-, L- and P-type VDCCs, as well as an antagonist at a non-L-, non-N-type site. Drugs were administered via chronic lumbar intrathecal, i.v. or regional nerve block catheters implanted in rats with Tactile Allodynia induced by tight ligation of the left fifth and sixth lumbar spinal nerves. Intrathecally delivered N-type VDCC (omega-conopeptides SNX239, SNX159 and SNX111) produced dose-dependent blockade of Tactile Allodynia. Intrathecal L-type (diltiazem, verapamil and nimodipine), non-N-, non-L-type (omega-conopeptide SNX230) and P-type (omega-agatoxin IVA) VDCC antagonists had no effect on pain behavior at the highest doses examined. No VDCC antagonist suppressed paw withdrawal when administered i.v. SNX239, although effective when administered intrathecally, was without effect when applied regionally to the injured portion of the nerve. These results emphasize the importance of N-type, but not L- or P- type, VDCCs in the spinal cord on systems mediating persistent Tactile Allodynia after nerve injury.
