TSUKAHARA Masato YAMAGUCHI UNIV. SCH. OF ALLIED HEALTH SCI, PROFESSOR, 医療技術短期大学部, 教授 (20136188)
FURUKAWA Syoei GIFU PHARMAC. COOL. PHARMACOLOGY, PROFESSOR, 薬学部, 教授 (90159129)
坂部 武史 山口大学, 医学部, 教授 (40035225)
中木村 和彦 山口大学, 医学部, 助教授 (50180261)
|Budget Amount *help
¥9,300,000 (Direct Cost : ¥9,300,000)
Fiscal Year 1999 : ¥3,600,000 (Direct Cost : ¥3,600,000)
Fiscal Year 1998 : ¥5,700,000 (Direct Cost : ¥5,700,000)
In pathological pain after peripheral nerve injury, the neuronal plasticity of the somatosensory system is recently thought to be directly involved. However, there are few report concerning with molecular and neurobiological mechanisms. The aimof the present study was to elucidate the molecular mechanism of pathological pain using well-established rat model, which may initiate perturbation of intracellular-nucleus processing resulting in increased Ca2+ caused by excessive release of glutamate and sP. In addition, it was to investigate possibilities for treatment resulting from these mechanisms including suppression of afferent input and synthesis of nerve growth factor.
Using rats the left sciatic nerve was ligated to induce the neuropathic pain. Under anesthesia loop-type microdialysis catheter was intrathecally implanted along with PE-10 tube for the spinal glutamate release (HPLC) and drug injection, respactively. For the treatment either (1) N-type Ca channel blocker (I.T.), (2) 5-H
T2A blocker (I.P.), or (3) 4-methyl cathechol (4-MC, I.P.) was respectively administered.
After sciatic nerve ligation, rats showed thermal hyperalgesia accompanied with increased spinal glutamate release and that was enhanced with time. There were c-fos protein induction and apoptosis of spinal cord neurons in the initial state of the hyperalgesia followed by the necrosis of the interneurons. N-type Ca channel blocker and 5-HT2A receptor antagonist significantly attenuates spinal glutamate release accompanied with decreased incidences of apoptosis and necrosis of interneurons at spinal cord. In addition, 4-MC administration, which brings about the synthesis induction of the nerve growth factor that it, attenuates the spinal glutamate release and that suppresses these histological changes.
Based on the present study, it is suggested that it generates modulation in the intrellular-nucleus process, which originates from the excessive excitation of the spinal cord glutamate nerve system and brings about the apoptosis, and that this is concerned in the manifestation in neuripathic pain. In addition, for the con version to chronic pain, it was indicated that the dysfunction of the interneuron was concerned, and promotes further understand mechanisms of the nerve - immuno network. In proves application of these treatments to the functional recovery in the clinical situation that the induction of the nerve growth factor restores the process for cell death in addition to the usefulness of peripheral 5-HT2A blocker and intrathecal N-type Ca channel blocker. In the future, it will be needed to examine whether transplantation and adeno-vector virus NGF administration are significant treatment for neuropathic pain. Less