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

Watanabe T, Sasaki M, Komagata S, Tsukano H, Hishida R, Kohno T, Baba H, Shibuki K - Sci Rep (2015)

Bottom Line: The reduction in the threshold was blocked by spinal application of LY354740, a specific agonist of group II metabotropic glutamate receptors.Potentiation already appeared during ischemic treatment for 30 min.The present findings suggest that the postischemic potentiation shares spinal mechanisms, at least in part, with neuropathic pain.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Neurophysiology, Brain Research Institute, Niigata University,1-757 Asahi-machi, Chuo-ku, Niigata 951-8585, Japan [2] Department of Anesthesiology, School of Medicine, Niigata University, 1-757 Asahi-machi, Chuo-ku, Niigata 951-8510, Japan.

ABSTRACT
Transient ischemia produces postischemic tingling sensation. Ischemia also produces nerve conduction block that may modulate spinal neural circuits. In the present study, reduced mechanical thresholds for hindpaw-withdrawal reflex were found in mice after transient hindpaw ischemia, which was produced by a high pressure applied around the hindpaw for 30 min. The reduction in the threshold was blocked by spinal application of LY354740, a specific agonist of group II metabotropic glutamate receptors. Neural activities in the spinal cord and the primary somatosensory cortex (S1) were investigated using activity-dependent changes in endogenous fluorescence derived from mitochondrial flavoproteins. Ischemic treatment induced potentiation of the ipsilateral spinal and contralateral S1 responses to hindpaw stimulation. Both types of potentiation were blocked by spinal application of LY354740. The contralateral S1 responses, abolished by lesioning the ipsilateral dorsal column, reappeared after ischemic treatment, indicating that postischemic tingling sensation reflects a sensory modality shift from tactile sensation to nociception in the spinal cord. Changes in neural responses were investigated during ischemic treatment in the contralateral spinal cord and the ipsilateral S1. Potentiation already appeared during ischemic treatment for 30 min. The present findings suggest that the postischemic potentiation shares spinal mechanisms, at least in part, with neuropathic pain.

No MeSH data available.


Related in: MedlinePlus

Mechanisms underlying postischemic plasticity.(a) Sensory modality shift from tactile to tingling sensation at the spinal cord level. (b) Schematic drawings of spinal potentiation ipsilateral and contralateral to ischemic treatment. Expected spinal potentiation induced after partial nerve cutting may also be induced by similar mechanisms.
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f6: Mechanisms underlying postischemic plasticity.(a) Sensory modality shift from tactile to tingling sensation at the spinal cord level. (b) Schematic drawings of spinal potentiation ipsilateral and contralateral to ischemic treatment. Expected spinal potentiation induced after partial nerve cutting may also be induced by similar mechanisms.

Mentions: An initial phase of neuropathic pain after partial denervation is abolished by spinal application of LY3547407, and this compound and similar group II mGluR agonists alleviate neuropathic pain841. Because the potentiation in the present study was also susceptible to spinal application of LY354740, these two types of potentiation may share similar mechanisms, at least in part, with neuropathic pain (Fig. 6a). Activation of postsynaptic group II mGluRs reduces presynaptic transmitter release42, produces membrane hyperpolarization by opening inward rectifier K+ channels4344, and modulates spontaneous Ca2+ spikes45. Therefore, failure of group II mGluR activation during conduction block of peripheral nerve activities may increase the excitability and intracellular Ca2+ concentration of postsynaptic neurons. These changes induce down-regulation of the neuron-specific KCl cotransporter (KCC2) in dorsal horn neurons and a resulting reduced neuronal Cl– gradient464748. Nociceptive spinal neurons are dynamically regulated by inhibition from various sources4950, and modulation of the Cl– gradient can explain the increased responsiveness of spinothalamic tract neurons to innocuous mechanical stimuli in animals with neuropathic pain4851. The spinal potentiation is induced not only in the ipsilateral site that fails to receive basal afferent firing, but also in the contralateral site or nearby site after partial nerve cutting. Because stimulation of different skin areas produces separate spinal responses (for example, Fig. 3), the potentiation in nearby spinal sites may have been induced by diffusible mediators produced in spinal neurons that failed to receive basal afferent firing (Fig. 6b). It is suggested that hindpaw ischemia produced some diffusible mediators that produced not only potentiation of contralateral hindpaw responses but also contralateral mechanical allodynia. Diffusible mediators may also play a role in potentiation of spinal responses ipsilateral to ischemic treatment. In accordance with this concept, neuropathic pain was reported to be facilitated by a number of diffusible mediators such as nitric oxide52 and ATP/cytokines53. The mechanical allodynia observed after hindpaw ischemia seemed to be more clearly observed in mice compared with similar phenomena in humans. Furthermore, humans do not clearly exhibit tingling sensation contralateral to the ischemic side or after partial nerve cutting. This difference may be attributed to the small size of spinal circuits in mice, in which diffusible messengers such as nitric oxide can be very effective. Another important consideration is that the potentiation observed during ischemic treatment in the present study could not be induced by repetitive activity in peripheral nerves, another condition known to induce spinal potentiation5455.


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

Watanabe T, Sasaki M, Komagata S, Tsukano H, Hishida R, Kohno T, Baba H, Shibuki K - Sci Rep (2015)

Mechanisms underlying postischemic plasticity.(a) Sensory modality shift from tactile to tingling sensation at the spinal cord level. (b) Schematic drawings of spinal potentiation ipsilateral and contralateral to ischemic treatment. Expected spinal potentiation induced after partial nerve cutting may also be induced by similar mechanisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499883&req=5

f6: Mechanisms underlying postischemic plasticity.(a) Sensory modality shift from tactile to tingling sensation at the spinal cord level. (b) Schematic drawings of spinal potentiation ipsilateral and contralateral to ischemic treatment. Expected spinal potentiation induced after partial nerve cutting may also be induced by similar mechanisms.
Mentions: An initial phase of neuropathic pain after partial denervation is abolished by spinal application of LY3547407, and this compound and similar group II mGluR agonists alleviate neuropathic pain841. Because the potentiation in the present study was also susceptible to spinal application of LY354740, these two types of potentiation may share similar mechanisms, at least in part, with neuropathic pain (Fig. 6a). Activation of postsynaptic group II mGluRs reduces presynaptic transmitter release42, produces membrane hyperpolarization by opening inward rectifier K+ channels4344, and modulates spontaneous Ca2+ spikes45. Therefore, failure of group II mGluR activation during conduction block of peripheral nerve activities may increase the excitability and intracellular Ca2+ concentration of postsynaptic neurons. These changes induce down-regulation of the neuron-specific KCl cotransporter (KCC2) in dorsal horn neurons and a resulting reduced neuronal Cl– gradient464748. Nociceptive spinal neurons are dynamically regulated by inhibition from various sources4950, and modulation of the Cl– gradient can explain the increased responsiveness of spinothalamic tract neurons to innocuous mechanical stimuli in animals with neuropathic pain4851. The spinal potentiation is induced not only in the ipsilateral site that fails to receive basal afferent firing, but also in the contralateral site or nearby site after partial nerve cutting. Because stimulation of different skin areas produces separate spinal responses (for example, Fig. 3), the potentiation in nearby spinal sites may have been induced by diffusible mediators produced in spinal neurons that failed to receive basal afferent firing (Fig. 6b). It is suggested that hindpaw ischemia produced some diffusible mediators that produced not only potentiation of contralateral hindpaw responses but also contralateral mechanical allodynia. Diffusible mediators may also play a role in potentiation of spinal responses ipsilateral to ischemic treatment. In accordance with this concept, neuropathic pain was reported to be facilitated by a number of diffusible mediators such as nitric oxide52 and ATP/cytokines53. The mechanical allodynia observed after hindpaw ischemia seemed to be more clearly observed in mice compared with similar phenomena in humans. Furthermore, humans do not clearly exhibit tingling sensation contralateral to the ischemic side or after partial nerve cutting. This difference may be attributed to the small size of spinal circuits in mice, in which diffusible messengers such as nitric oxide can be very effective. Another important consideration is that the potentiation observed during ischemic treatment in the present study could not be induced by repetitive activity in peripheral nerves, another condition known to induce spinal potentiation5455.

Bottom Line: The reduction in the threshold was blocked by spinal application of LY354740, a specific agonist of group II metabotropic glutamate receptors.Potentiation already appeared during ischemic treatment for 30 min.The present findings suggest that the postischemic potentiation shares spinal mechanisms, at least in part, with neuropathic pain.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Neurophysiology, Brain Research Institute, Niigata University,1-757 Asahi-machi, Chuo-ku, Niigata 951-8585, Japan [2] Department of Anesthesiology, School of Medicine, Niigata University, 1-757 Asahi-machi, Chuo-ku, Niigata 951-8510, Japan.

ABSTRACT
Transient ischemia produces postischemic tingling sensation. Ischemia also produces nerve conduction block that may modulate spinal neural circuits. In the present study, reduced mechanical thresholds for hindpaw-withdrawal reflex were found in mice after transient hindpaw ischemia, which was produced by a high pressure applied around the hindpaw for 30 min. The reduction in the threshold was blocked by spinal application of LY354740, a specific agonist of group II metabotropic glutamate receptors. Neural activities in the spinal cord and the primary somatosensory cortex (S1) were investigated using activity-dependent changes in endogenous fluorescence derived from mitochondrial flavoproteins. Ischemic treatment induced potentiation of the ipsilateral spinal and contralateral S1 responses to hindpaw stimulation. Both types of potentiation were blocked by spinal application of LY354740. The contralateral S1 responses, abolished by lesioning the ipsilateral dorsal column, reappeared after ischemic treatment, indicating that postischemic tingling sensation reflects a sensory modality shift from tactile sensation to nociception in the spinal cord. Changes in neural responses were investigated during ischemic treatment in the contralateral spinal cord and the ipsilateral S1. Potentiation already appeared during ischemic treatment for 30 min. The present findings suggest that the postischemic potentiation shares spinal mechanisms, at least in part, with neuropathic pain.

No MeSH data available.


Related in: MedlinePlus