The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury

Kalmár, Bernadett; Greensmith, Linda; Malcangio, Marzia; McMahon, Stephen B.; Csermely, Péter; Burnstock, Geoffrey

doi:10.1016/s0014-4886(03)00343-1

Cited by 60 publications

(41 citation statements)

References 30 publications

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“…Mechanical hypersensitivity was assessed with a Dynamic Plantar Aesthesiometer (Ugo Basile, Comerio, Italy), which is an automated von Frey-type system (Kalmar et al 2003;Lever et al 2003). To measure animal hindpaw mechanical thresholds, animals were placed in plastic cages with a wire mesh floor and allowed to acclimate for 15 min before each test session.…”

Section: Behavioral Testsmentioning

confidence: 99%

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

Obata

Katsura

Miyoshi

et al. 2008

Journal of Neurochemistry

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Toll-like receptors (TLRs) play an essential role in innate immune responses and in the initiation of adaptive immune responses. Microglia, the resident innate immune cells in the CNS, express TLRs. In this study, we show that TLR3 is crucial for spinal cord glial activation and tactile allodynia after peripheral nerve injury. Intrathecal administration of TLR3 antisense oligodeoxynucleotide suppressed nerve injury-induced tactile allodynia, and decreased the phosphorylation of p38 mitogen-activated protein kinase, but not extracellular signal-regulated protein kinases 1/2, in spinal glial cells. Antisense knockdown of TLR3 also attenuated the activation of spinal microglia, but not astrocytes, caused by nerve injury. Furthermore, down-regulation of TLR3 inhibited nerve injuryinduced up-regulation of spinal pro-inflammatory cytokines, such as interleukin-1b, interleukin-6, and tumor necrosis factor-a. Conversely, intrathecal injection of the TLR3 agonist polyinosine-polycytidylic acid induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury. Indeed, TLR3-deficient mice did not develop tactile allodynia after nerve injury or polyinosine-polycytidylic acid injection. Our results indicate that TLR3 has a substantial role in the activation of spinal glial cells and the development of tactile allodynia after nerve injury. Thus, blocking TLR3 in the spinal glial cells might provide a fruitful strategy for treating neuropathic pain.

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Section: Behavioral Testsmentioning

confidence: 99%

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

Obata

Katsura

Miyoshi

et al. 2008

Journal of Neurochemistry

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“…All PSNL rats were tested for mechanical allodynia and thermal hyperalgesia on the plantar surface of the hindpaw 1 d before surgery and 1, 3, 5, 7, 10, and 12 d after surgery. Mechanical allodynia was assessed with a dynamic plantar anesthesiometer (Ugo Basile, Comerio, Italy), which has an automated von Frey-type filament (0.5 mm diameter) (Kalmar et al, 2003;Lever et al, 2003). To measure mechanical thresholds of the hindpaw, rats were placed in a plastic cage with a wire mesh floor and allowed to acclimate for 15 min before each test session.…”

Section: Methodsmentioning

confidence: 99%

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Kobayashi¹,

Yamanaka²,

Fukuoka³

et al. 2008

J. Neurosci.

257

238

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Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y 12 , has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury.Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y 12 mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y 12 mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y 12 antagonist and antisense knockdown of P2Y 12 expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y 12 agonist 2-(methythio) adenosine 5Ј-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors.These data suggest a new mechanism of neuropathic pain, in which the increased P2Y 12 works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.

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“…All rats were tested for mechanical allodynia and thermal hyperalgesia of the plantar surface of the hindpaw 1 d before surgery and 3, 7, or 14 d after surgery. Mechanical allodynia was assessed with a dynamic plantar aesthesiometer (Ugo Basile, Comerio, Italy), which is an automated von Frey-type system (Kalmar et al, 2003;Lever et al, 2003). To measure rat hindpaw mechanical thresholds, rats were placed in plastic cages with a wire mesh floor and allowed to acclimate for 15 min before each test session.…”

Section: Methodsmentioning

confidence: 99%

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Obata¹,

Yamanaka²,

Kobayashi³

et al. 2004

J. Neurosci.

290

208

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To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small-to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.

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The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury

Cited by 60 publications

References 30 publications

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

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The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury

Cited by 60 publications

References 30 publications

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

THIS ARTICLE HAS BEEN RETRACTED: Toll‐like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

P2Y12Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

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Product

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P2Y₁₂Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain