Temozolomide Attenuates Neuropathic Pain caused by Nerve Injury

• Main Authors: Ping-Luen Chen, 陳品綸
• Other Authors: Ling-LI Zheng
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/02735939287827581635

碩士 === 高雄醫學大學 === 醫學研究所碩士班 === 103 === Background: Neuropathic pain caused by peripheral nerve injury is closely associated with the pathogenesis of pain hypersensitivity of microglia and astrocytes in spinal dorsal horn (SDH). Temozolomide (TMZ) demonstrates great efficacy for astrocytoma, however, limited information is known if TMZ is also efficacious for neuropathic pain caused by nerve injury. Aim: To assess if TMZ application could suppress the glial cell activation and proliferation in central neural system, and reduce the change of sodium channels in dorsal root ganglia (DRG) and the nociceptors transient receptor potential cation channel subfamily V member 1 (TRPV1) activation. Material and methods: Sprague-Dawlay (SD) rats were randomly divided into four groups: (1) normal group (group N), no surgery and no TMZ administration; (2) ligation group (group SNL + Vehicle; group LV), L5 spinal nerve ligation with intrathecal injection of normal saline; (3) intrathecal TMZ group (group SNL + TMZ (I.T.); group LTi), L5 spinal nerve ligation with intrathecal TMZ (100μg/ml) for 7 days; (4) oral TMZ group (group SNL + TMZ; group LTp), L5 spinal nerve ligation with oral TMZ (200μg/m2) for 5 days. Neuropathic pain was assessed by responses to mechanical and thermal stimuli. Activation of astrocytes and microglia in SDH, dysregulated voltages of sodium channels Nav1.3, 1.7 and 1.8 and activated TRPV1, expression of injured dorsal root ganglion neurons marker ATF-3 in DRG were measured by western blot and immunofluorescence on postoperative 7 and 14 day (POD7 and POD14). Result: Following SNL, mechanical allodynia and thermal hyperalgesia following nerve injury were found , microglia and astrocytes in SDH were activated, Nav1.3, TRPV1 and ATF3 were upregulated with downregulation of Nav1.8, in DRG. TMZ administration can alleviate mechanical allodynia and thermal hyperalgesia. Oral TMZ administration was more effective than intrathecal TMZ administration on attenuation of behavioral hypersensitivity and the effect lasted for 14 days. Additionally, TMZ administration decreased astrocytes but not microglia activation in SDH, downregulated Nav1.3, TRPV1 and ATF3 in DRG on POD7. Moreover, the effect of TMZ in decreasing TRPV1 and ATF3 can last for 14 days. Conclusion: Oral TMZ administration provide better effect than intrathecal TMZ administration in alleviating neuropathic pain, downregulating astrocyte activation in SDH, decreasing ATF3、Nav1.3 and TRPV1 expression in DRG.