Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system

Otsubo, Yukiko; Satoh, Yasushi; Kodama, Mitsuyoshi; Araki, Yoshiyuki; Satomoto, Maiko; Shimizu, Eiji; Pagès, Gilles; Pouysségur, Jacques; Endo, Shogo; Kazama, Tomiei

doi:10.1016/j.pain.2012.07.020

Cited by 30 publications

(40 citation statements)

References 34 publications

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“…Throughout the experiment, we used a partial sciatic nerve ligation (PSNL) model as a neuropathic pain model (Seltzer model) as described previously [17]. Briefly, the sciatic nerve located in the right hind paw was exposed via a small incision and approximately 1/3–1/2 the diameter of the nerve was tightly ligated with an 8–0 silk suture.…”

Section: Methodsmentioning

confidence: 99%

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Molecular Hydrogen Attenuates Neuropathic Pain in Mice

et al. 2014

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Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting.

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Section: Methodsmentioning

confidence: 99%

“…To quantify mechanical allodynia, paw withdrawal responses to mechanical stimulation were assessed with von Frey filaments as previously described [17]. Briefly, mice were habituated for at least 1 h prior to testing in a clear acrylic cylinder (20 cm in height and 10 cm in diameter) on an elevated mesh floor.…”

Section: Methodsmentioning

confidence: 99%

Molecular Hydrogen Attenuates Neuropathic Pain in Mice

et al. 2014

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“…Previous reports show that thermal and mechanical hypersensitivities resulting from NGF differ from each other, both in time course - mechanical hypersensitivity lasting much longer (Mills et al, 2013) - and in central MAPKinase involvement (Ostubo et al, 2012) In an earlier paper we detailed the receptor and pathway intermediates involved in mechano-sensitization by NGF, when injected as in the present study (Khodorova et al, 2013). The initial steps in signaling for this sensory modality differ completely from those for thermal hyperalgesia, mechano-sensitization requiring neurotrophin binding to the p75 NTR and activation of nSMase, neither of which is involved in the thermal response.…”

Section: Discussionmentioning

confidence: 71%

“…The combined evidence suggests that PKMζ activity in both the periphery and the spinal cord contributes to thermal and mechanical hyperalgesia, although the pathways for activation may differ between these two modalities (Ostubo et al, 2012), and between peripheral and central loci (see Lewin et al, 1994). …”

Section: Discussionmentioning

confidence: 99%

The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor

2017

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The p75 neurotrophin receptor (p75NTR) and its activation of the sphingomyelin signaling cascade are essential for mechanical hypersensitivity resulting from locally injected nerve growth factor (NGF). Here the role of the same effectors, and of the TrkA receptor, are evaluated for thermal hyperalgesia from NGF. Sensitivity of rat hind paw plantar skin to thermal stimulation after local sub-cutaneous injection of NGF (500 ng) was measured by the latency for paw withdrawal (PWL) from a radiant heat source. PWL was reduced from baseline values at 0.5–22h by ~40% from that in naïve or vehicle-injected rats, and recovered to pre-injection levels by 48h. Local pre-injection with a p75NTR blocking antibody did not affect the acute thermal hyperalgesia (0.5–3.5h) but hastened its recovery so that it had reversed to baseline by 22h. In addition, GW4869 (2 mM), an inhibitor of the neutral sphingomyelinase (nSMase) that is an enzyme in the p75NTR pathway, also failed to prevent thermal hyperalgesia. However, C2-ceramide, an analogue of the ceramide produced by sphingomyelinase, did cause thermal hyperalgesia. Injection of an anti-TrkA antibody known to promote dimerization and activation of that receptor, independent of NGF, also caused thermal hyperalgesia, and prevented the further reduction of PWL from subsequently injected NGF. A nonspecific inhibitor of tropomyosin receptor kinases, K252a, prevented thermal hyperalgesia from NGF, but not that from the anti-TrkA antibody. These findings suggest that the TrkA receptor has a predominant role in thermal hypersensitivity induced by NGF, while p75NTR and its pathway intermediates serve a modulatory role.

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“…Evidence has shown that extracellular signal-regulated kinase (ERK) plays a decisive role in regulating inflammatory responses and neuropathic pain [22, 23]. A recent study also reported that ERK knockout mice exhibited decreased pain sensitization after formalin stimulation or partial sciatic nerve ligation [24]. Thus, inhibition of ERK activation may be a promising therapeutic target for the treatment of neuropathic pain [25–27].…”

Section: Introductionmentioning

confidence: 99%

Association between extracellular signal-regulated kinase expression and the anti-allodynic effect in rats with spared nerve injury by applying immediate pulsed radiofrequency

et al. 2015

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BackgroundThe application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI).MethodsNeuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3–0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups.ResultsThe three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery.ConclusionsImmediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.

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Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system

Cited by 30 publications

References 34 publications

Molecular Hydrogen Attenuates Neuropathic Pain in Mice

Molecular Hydrogen Attenuates Neuropathic Pain in Mice

The TrkA receptor mediates experimental thermal hyperalgesia produced by nerve growth factor: Modulation by the p75 neurotrophin receptor

Association between extracellular signal-regulated kinase expression and the anti-allodynic effect in rats with spared nerve injury by applying immediate pulsed radiofrequency

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