神経因性疼痛の発症・維持機構における脊髄神経可塑性の役割 : 脊髄神経伝達および細胞内シグナリング変調における新規Ca^<2+>チャネル阻害薬の効果
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The mechanism of neuropathic pain following peripheral nerve injury has not been fully understood. Recent investigations suggested that glutamate-mediated activation of spinal cord neurons might be a pivotal mechanism to induce central sensitization. Following peripheral nerve injury, glutamatergic neuronal activation evokes repetitive stimulation of targeted receptor, NMDA and AMPA receptors followed by intracellular signaling, including early gene c-fos expression. However, there is no direct observation of spinal glutamate release and c-fos expression in relation to pain behavior. N-type Ca channels are especially located at terminal of c-fiber and Aβ-fiber, and it is thought to modulate afferent nociceptive processing. Therefore, the present study was designed to characterize the effect of a novel N-type Ca channel blocker, ONO-2921 on the thermal hyperalgesia in relation to concomitant spinal CSF glutamate release and expression of c-fos protein of dorsal horn neurons. Male Spague-Dawley rats were intrathecally implanted with microdialysis probe. Three days later, the left sciatic nerve was loosely ligated (chronic constriction injury: CCI). The paw withdrawal latency (PWL) against thermal stimulation was periodically measured after CCI. On days 5 and 10, the intrathecal microdialysis was conducted for measuring CSF glutamate release evoked by thermal stimulation to hind paw. After completion of measurements, per fusion fixation was performed for immunohistochemistry (c-fos protein) and HE stains. ONO-2921 (100 mg, po) alone or together with BayK-8644 (agonist of L-type Ca channel) was periodically given at 5 days after CCI operation. Following CCI the PWL of injured leg was decreased with time observed from day 3 to day 10. On day 10, CSF glutamate releases evoked by thermal stimulation was increased by 20%. The c-fos positive-immunoreactivity at Rexed I-n was profoundly allowed accompanied with neuronal damage of Rexed III-IV. These changes were significantly attenuated with ONO-2921. This effect of ONO-2921 was not reversed by i. t. Bay K-8644. Based on the present study, it is suggested that the increased CSF-glutamate release after peripheral nerve injury may cause perturbation of synaptic transmission, including CSF-glutamate release followed by c-fos expression of neurons which is so-called "neuroplasticity" of spinal cord neuronal system and that this repetitive neuronal activation of wide-dynamic range neurons develops neuropathic pain. A novel N-type Ca channel blocker ONO-2921 has attenuating effect of afferent nociceptive processing which is decrease of CSF glutamate release in relation to c-fos expression.
- 九州歯科学会の論文
- 2003-04-25
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- 神経因性疼痛の発症・維持機構における脊髄神経可塑性の役割 : 脊髄神経伝達および細胞内シグナリング変調における新規Caチャネル阻害薬の効果(九州歯科大学大学院歯学研究科博士論文の内容および審査の結果)
- 神経因性疼痛の発症・維持機構における脊髄神経可塑性の役割 : 脊髄神経伝達および細胞内シグナリング変調における新規Ca^チャネル阻害薬の効果