Spinal mechanisms underlying potentiation of hindpaw responses observed after transient hindpaw ischemia in mice

Watanabe, Tatsunori; Sasaki, Mika; Komagata, Seiji; Tsukano, Hiroaki; Hishida, Ryuichi; Kohno, Tatsuro; Baba, Hiroshi; Shibuki, Katsuei

doi:10.1038/srep11191

Cited by 6 publications

(19 citation statements)

References 55 publications

(82 reference statements)

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“…Mice were operated on as described previously (Watanabe et al . ). They were anaesthetized with urethane (1.65 g/kg, i.p.…”

Section: Methodsmentioning

confidence: 97%

“…), and hindpaw ischaemia and the resulting conduction block of peripheral nerves induce cortical/spinal potentiation within 30 min (Watanabe et al . ). Therefore, it is natural to assume that similar neural mechanisms are responsible for both types of acute potentiation after partial nerve cutting and ischaemic conduction block.…”

Section: Introductionmentioning

confidence: 97%

“…Similarly, spatial spreading is observed in the potentiation that follows hindpaw ischaemia: potentiation is induced on the contralateral side of ischaemic conduction block, as well as on the ipsilateral side (Watanabe et al . ). Spatial spreading is also a characteristic feature of neuropathic pain: it is observed in sites distant from the site of nerve injury (Milligan et al .…”

Section: Introductionmentioning

confidence: 97%

“…The mouse may be an ideal experimental animal model for testing the third possibility, because the mouse spinal cord is sufficiently small that influences of unilaterally produced diffusible mediators can be detected on the other side of the spinal cord (Watanabe et al . ).…”

Section: Introductionmentioning

confidence: 97%

“…) and ischaemic conduction block (Watanabe et al . ), as in neuropathic pain (Simmons et al . ; Jones et al .…”

Section: Introductionmentioning

confidence: 99%

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Acute spatial spread of NO‐mediated potentiation during hindpaw ischaemia in mice

Onishi

Watanabe

Sasaki

et al. 2019

The Journal of Physiology

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Key points Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord.However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation.In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischaemia are nitric oxide (NO)‐dependent and that NO is produced by ischaemia and quickly diffuses within the spinal cord.We also found that NO production induced by ischaemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase‐positive dorsal horn neurons express group II mGluRs.These results suggest strongly that NO‐mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain. AbstractCortical/spinal responses to hindpaw stimulation are bilaterally potentiated by unilateral hindpaw ischaemia in mice. We tested the hypothesis that hindpaw ischaemia produces nitric oxide (NO), which diffuses in the spinal cord to induce spatially spreading potentiation. Using flavoprotein fluorescence imaging, we confirmed that the spreading potentiation in hindpaw responses was induced during ischaemia in the non‐stimulated hindpaw. This spreading potentiation was blocked by spinal application of l‐NAME, an inhibitor of NO synthase (NOS). Furthermore, no spreading potentiation was observed in neural NOS (nNOS) knockout mice. Spinal application of an NO donor was enough to induce cortical potentiation and mechanical hypersensitivity. The spatial distribution of NO during unilateral hindpaw ischaemia was visualized using 4‐amino‐5‐methylamino‐2′,7′‐difluorofluorescein (DAF‐FM). An increase in fluorescence derived from the complex of DAF‐FM with NO was observed on the ischaemic side of the spinal cord. A similar but smaller increase was also observed on the contralateral side. Somatosensory potentiation after hindpaw ischaemia is known to be inhibited by spinal application of LY354740, an agonist of group II metabotropic glutamate receptors (mGluRs). We confirmed that the spinal DAF‐FM fluorescence increases during hindpaw ischaemia were not observed in the presence of LY354740. We also confirmed that approximately half of the nNOS‐positive neurons in the superficial laminae of the dorsal horn expressed mGluR2 mRNA. These results suggest that disinhibition of mGluR2 produces NO which in turn induces a spreading potentiation in a wide area of the spinal cord. Such spreading, along with the consequent non‐specific potentiation in the spinal cord, may trigger neuropathic pain.

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“…Mice were operated on as described previously (Watanabe et al . ). They were anaesthetized with urethane (1.65 g/kg, i.p.…”

Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

“…) and ischaemic conduction block (Watanabe et al . ), as in neuropathic pain (Simmons et al . ; Jones et al .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Acute spatial spread of NO‐mediated potentiation during hindpaw ischaemia in mice

Onishi

Watanabe

Sasaki

et al. 2019

The Journal of Physiology

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MiR-187-3p mimic alleviates ischemia-reperfusion-induced pain hypersensitivity through inhibiting spinal P2X7R and subsequent mature IL-1β release in mice

Zhang

et al. 2019

Brain, Behavior, and Immunity

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Quantitative map of multiple auditory cortical regions with a stereotaxic fine-scale atlas of the mouse brain

Tsukano

Horie

Hishida

et al. 2016

Sci Rep

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Optical imaging studies have recently revealed the presence of multiple auditory cortical regions in the mouse brain. We have previously demonstrated, using flavoprotein fluorescence imaging, at least six regions in the mouse auditory cortex, including the anterior auditory field (AAF), primary auditory cortex (AI), the secondary auditory field (AII), dorsoanterior field (DA), dorsomedial field (DM), and dorsoposterior field (DP). While multiple regions in the visual cortex and somatosensory cortex have been annotated and consolidated in recent brain atlases, the multiple auditory cortical regions have not yet been presented from a coronal view. In the current study, we obtained regional coordinates of the six auditory cortical regions of the C57BL/6 mouse brain and illustrated these regions on template coronal brain slices. These results should reinforce the existing mouse brain atlases and support future studies in the auditory cortex.

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Spinal mechanisms underlying potentiation of hindpaw responses observed after transient hindpaw ischemia in mice

Cited by 6 publications

References 55 publications

Acute spatial spread of NO‐mediated potentiation during hindpaw ischaemia in mice

Acute spatial spread of NO‐mediated potentiation during hindpaw ischaemia in mice

MiR-187-3p mimic alleviates ischemia-reperfusion-induced pain hypersensitivity through inhibiting spinal P2X7R and subsequent mature IL-1β release in mice

Quantitative map of multiple auditory cortical regions with a stereotaxic fine-scale atlas of the mouse brain

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