神経因性疼痛の発症・維持機構における脊髄グルタメート放出の関与 : Cilnidipine による修飾作用

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The mechanisms of neuropathic pain developed following peripheral nerve injury have not been fully elucidated. As to recent findings, the one of the pivotal mechanisms is thought to be glutamate toxicity of spinal cord neurons due to repetitive nerve stimulation originating from the injured region. Therefore, a possible way to clarify is a direct observation of spinal glutamate release evoked by peripheral nerve injury. In the present study, we examined whether enhanced cerebrospinal fluid glutamate (CSF-Glu) release leads to neuropathic pain in relation to neuronal damages after chronic constriction injury (CCI) in rats, by using spinal microdialysis technique. Regardingly, we confirmed a possibility that N-type Ca^<2+> channel blocker cilnidipine inhibits the CSF-Glu release accompanied with pain behaviour and cell damages. Male Sprague-Dawley rats were anesthetized with halothane and were intrathecally implanted with a loop-type microdialysis probe to detect CSF-aminoacids and PE 10 tube to inject cilnidipine, prior to following the experiments. Thereafter, the left sciatic nerve was loosely ligated according to the method by Bennett et.al (1988). Paw withdrawal latency (PWL) times of response to thermal stimulation were measured by planter testing before CCI followed by 3, 5, 7, and 10 days after CCI. Rats were separated into three groups. : 1) sham group 2) non-treated group (saline 10μl) 3) Cilnidipine group (cilnidipine 100ng/10μl). Each drug of 10μl was injected by PE10 tube everyday from 3 days after CCI. On day 5 and 10, microdialysis was conducted for measuring of CSF-Glu, taurine and serine by HPLC-ECD. After the microdialysis, perfusion fixation was performed under halothane anesthesia, and spinal cord tissue was removed following hematoxilin and eosin staining for assessment of neuronal necrosis with light microscope. The results showed that the responses to thermal stimulation to PWL in non-treated group were increased with time appearing from day 3 until day 10. On day 10, CSF-Glu release increased by 129% during the first 10 min and gradually declained to 116% during the next 10 min. Neuronal damage appeared specifically in Rexed III-IV with time. Cilnidipine ameliorated significantly the shortend PWL and the increased CSF-Glu release by thermal stimulation, and the neuronal damage in Rexed III-IV after CCI. Based on the present study, it is concluded that the increases in spinal glutamate release may initiate neuronal damage which leads neuropathic pain following nerve injury, in the dorsal horn of the spinal cord. In addition, it is suggested that beneficial effect of cilnidipine for developing neuropathic pain may be through mechanisms of inhibiting CSF-Glu release.
九州歯科学会の論文
2002-04-25

神経因性疼痛の発症・維持機構における脊髄グルタメート放出の関与 : Cilnidipine による修飾作用

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