大鼠脊髓胶质细胞参与骨癌痛的机理及鞘内丙戊茶碱的抗痛敏效应
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摘要
第一部分大鼠骨癌痛模型的建立与评价
目的探讨腹水传代与体外培养Walker-256细胞接种建立SD大鼠骨癌痛模型的可行性,并从多方面验证其稳定性与可靠性。方法体外培养与大鼠腹水传代增殖Walker-256细胞,种植于SD大鼠左胫骨上端。大鼠均分为Hank液对照组(NI组);热杀死肿瘤细胞(K1组);体外培养的肿瘤细胞种植组(V1组);腹水肿瘤细胞种植组(A1组),每组8只。通过疼痛行为学、镇痛药理学、影像学、病理组织学等评估肿瘤及疼痛发生发展情况。结果大鼠接种后肛温无明显变化。A1组与V1组术后第6天开始左侧后肢活动度开始下降,X摄片可见左胫骨上端骨小梁小缺损;第12天X摄片示骨皮质有破坏,SPECT可见接种区反应性骨形成活跃:第15天增重开始减缓:第18天X摄片显示大片骨质缺损,软组织肿块形成,左胫骨病理切片示骨癌细胞生长。大鼠接种后第6天到第18天,机械性压爪缩爪阈值、von Frey值进行性下降(P＜0.01),双下肢负重差进行性增高(P＜0.01)。术后第15天注射吗啡后模型大鼠机械性压爪缩爪阈值呈剂量依赖性增高,而纳洛酮可拮抗此效应。结论经腹水传代与体外培养Walker 256细胞均可用于SD大鼠骨癌痛模型的建立;经腹水传代建模更为简便:细胞接种后第6-18天产生进行性增高的机械性痛觉过敏与痛觉超敏,而热痛觉过敏相对较轻;该模型适宜于骨癌痛机制及镇痛药理学的研究。
第二部分骨癌痛大鼠脊髓胶质细胞及其表达的变化
研究证实神经损伤与组织炎症时疼痛的产生与维持与脊髓胶质细胞激活有关。然而,在骨癌痛时脊髓胶质细胞的改变及其作用尚不清楚。目的了解雌性SD大鼠一侧胫骨注射同系Walker 256癌细胞后脊髓胶质细胞的变化,从而研究骨癌痛产生与维持的机制。方法应用大鼠体内腹水传代Walker 256乳腺癌细胞种植于一侧胫骨建立骨癌痛模型,雌性SD大鼠,体重为150-180g,随机均分为5组,每组5只:对照(N2)组、热杀死肿瘤细胞(K2)组、不同时间骨癌痛3组(A2-d6,A2-d12,A2-d18)。
结果骨癌痛大鼠L4～L6两侧脊髓星形胶质细胞与小胶质细胞显著增加并激活,表现为胶质纤维酸性蛋白(GFAP)和小胶质细胞标志物OX-42免疫组化染色显著增强,尤其以后角Ⅰ-Ⅱ层最为显著,围绕脊髓中央管附近(X层)也有显著着色,细胞明显增大,与N2组及K2组比较,差异均有统计学意义(P＜0.05,P＜0.01);其中GFAP染色术后第6-18天呈进行性增高,以A2-d18组最为显著,与A2-d6组比较,P＜0.01;OX-42染色术后第6-18天呈进行性降低,以A2-d6组最为显著(P＜0.05,P＜0.01)。
结论胫骨注射Walker 256肿瘤细胞后激活脊髓胶质细胞,这可能与自发痛行为、痛觉过敏及痛觉超敏有关。其次,星形胶质细胞与小胶质细胞在两侧脊髓灰质均有激活,可能反映了本模型骨癌痛特征中“镜像痛”的产生机制。脊髓小胶质细胞激活在骨癌痛产生中可能起主要作用,而星形胶质细胞激活在骨癌痛维持中可能起重要作用。
第三部分鞘内注射丙戊茶碱对大鼠骨癌痛的镇痛与抗痛敏作用及其脊髓机理
目的探讨鞘内注射丙戊茶碱(PPF)对大鼠骨癌痛的镇痛、抗痛觉过敏与抗痛觉超敏作用,并通过脊髓胶质细胞、磷酸化细胞外信号调节蛋白激酶的变化研究其作用的脊髓部位机理。方法40只SD大鼠以随机数字法均分为4组,每组10只:对照组(N3)、PPF组(P3)、左胫骨癌细胞种植组(A3)、左胫骨癌细胞种植+鞘内PPF治疗组(PA3)。手术后第9-12天每日1次鞘内分别注射生理盐水μl、PPF 10μg或生理盐水10μl。给药前后分别行von Frey值测定,术后第12天鞘内注药4小时后,分别行脊髓免疫组化染色及Western blot分析。结果与A3组比较,PA3组鞘内注射PPF后3h、4h、5h机械性痛阈值明显增高(P＜0.01);术后第9-12天PA3组每日鞘内注射PPF后,机械性痛阈值均有显著增高(P＜0.01)。与A3组相比,PA3组星形胶质细胞数量减少,胞体减小,染色变浅,突起减少(P＜0.05,P＜0.01);PA3组小胶质细胞胞体减小,数量减少,染色变浅,突起增多(P＜0.05,P＜0.01);PA3组p-ERK颗粒明显减少,染色变浅,颗粒变小(P＜0.05,P＜0.01)。结论鞘内注射PPF10μg对大鼠骨癌痛具有一定的镇痛、抗痛觉过敏与抗痛觉超敏作用;鞘内注射PPF通过抑制星形胶质细胞及小胶质细胞的激活,同时抑制脊髓背角ERK磷酸化而产生镇痛与抗痛敏作用。
Part I Study of A SD Rat Model of Bone Cancer Pain Created by Using Walker 256 Cultured in Vitro or in Vivo
Objective To investigate the possibility and verify the reliability of a SD rat model of bone cancer pain using Walker 256 cultivate in Vitro or in Vivo. Methods Bone cancer pain model was created by receiving left superior extremity intra-tibial inoculations of Walker 256 syngeneic SD rat carcinoma cells which culture and proliferation in vitro(group V1) or in vivo to produce ascites (group A1) in female SD rats weighing 150-180g,n=8. Rat of group N1 or group K1 were inoculated of Hank's or heat-killed cells. The development of bone tumour and pain were observated by digital radiology, ECT, MRI, histology, pain behavioural signs indicative of pain and analgesic pharmacodynamics. Results Rats of four groups did not show changes in body weight during 18 days. Rats of group A and group V displayed decrease of left hint limb activity and minute defect of bone trabecula in the proximal epiphysis by radiological analysis by day 6; Further deterioration was detected at day 12 post-injection with full thickness unicortical bone loss by radiological analysis and bone formation active in region by SPECT; Rats of group A and group V displayed signs of weight loss by day 15. At the final time point, 18 days after the cells injection, full thickness bicortical bone loss and form soft tissue tumor were observed by X ray. Bones inoculated with live cells showed infiltration of bone marrow spaces by malignant tumor on day 18 after inoculation in histology. Rats of group A and group V displayed the gradual development reduced of PWT, von Frey threshold and weight bearing of left hind limb between day 6 and day 18(P <0.01) .Morphine (2-16 mg/kg, S.C.) produced a dose-dependent reduction and Naloxone antagonist manner in the response frequency of hind paw withdrawal to Mechanical stimulation on 15 day following intra-tibia inoculation. Conclusions These results suggested that SD rat model of bone cancer pain can be established by using Walker 256 Culture in Vitro or in Vivo , and the latter was more convenient; the gradual development of mechanical allodynia and mechanical hyperalgesia and reduced of weight bearing on the affected limb, beginning on day 6 following inoculation, whereas the thermal hyperalgesia was not significant; Behavioral data suggest a reasonable time window for study the mechanism of bone cancer pain and evaluation of antinociceptive agents between day 6 and 18 after walker 256 inoculations.
Part II Spinal Glia Cell Activation in The SD Rat Model of Bone Cancer Pain Produced by Walker 256 Cancer Cell Inoculation in Tibia
Investigations demonstrated that glial activation in the spinal cord are involved in the development and persistent of pain induced by nerve injury and tissue inflammation. However, the alteration and role of glial cells in spinal cord of bone cancer pain is not well understood. Objective This study explored the spinal glial alteration in a rat model of bone cancer pain produced by injecting syngeneic Walker 256 rat mammary gland Cancer cells into the unilateral tibia of female SD rats. Thereby desire to study the mechanism of development and persistent of bone cancer pain. Methods Bone cancer pain model was created by receiving left superior extremity intra-tibial inoculations of Walker 256 syngeneic SD rat carcinoma cells which culture and proliferation in vivo to produce ascites (A2) in 25 female SD rats weighing 150-180g. The rats were divided by 5 groups randomly which included group N2(control), group K2 (inoculated of heat-killed cells) and group A2, and group A2 was consisted of A2(d6), A2d(12) and A2d(18) groups depended on the day of post inoculation. Results The results showed that astrocytes and microglia were significantly enhanced and activated in the L4-L6 superficial spinal cord bilateralis in rats of inoculation of Walker cancer cells, characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker, P <0.05, P <0.01) and OX-42 (microglial marker,P <0.05, P <0.01). Spinal GFAP staining progression increase on day 6 to day 18 post cell inoculation, and it was prominent on day of 18 postoperation (P <0.05, P <0.01). While Spinal OX-42 staining progression decrease on day 6 to day 18 post cell inoculation, and it was distinguished on day 6 post inoculation (P <0.05, P <0.01). Conclusions These results demonstrate that injection of Walker 256 cancer cells into the tibia activates the spinal glial cells, which may contribute to hyperalgesia and allodynia. Furthermore, the astrocytes and microglia activated in ipsi- and Contralateral superficial dorsal horns highlights the possible involvement in the mirror imaging pain phenomenon in neuroethology of this model of bone cancer pain.
Part III Anti-nociceptive and Anti-hyperalgesic Effect of Intrathecal Propentofylline on A Rat Model of Bone Cancer Pain and Its Mechanism in Spinal Cord
Objective The present study was undertaken to determine whether intrathecal injection propentofylline, a glial modulating agent, could generate anti-nociceptive, anti-hyperalgesic and anti-allodynic effect on a rat model of bone cancer pain. Moreover, investigate its effective mechanism through the alteration of spinal glial and p-ERK in spinal cord. Methods 40 SD rats were divided by 4 groups(n=10) randomly which included group N3(control), group P3 (intrathecal injection PPF 10μg), group A3(model of bone cancer pain and 0.9%NS intrathecal injection), and group PA3 (model of bone cancer pain and PPF 10μg intrathecal injection). Propentofylline or 0.9% was administered daily intrathecally during 9-12 day postoperation. Determination of von Frey threshold before and after intrathecal administered. Spinal cords (L4-L6 segments) were removed for immunohistochemical stainning and Western blot analysis 4h after intrathecal injection on day 12 post operation. Results The von Frey threshold in group PA3 was increased obviously during 3-5 h post PPF intrathecal injection compare to that in group A3 (P <0.01) , and the pain threshold was increased after PPF i.t. daily during 9-12d post inoculation. GFAP stained astrocyte were atrophied and become less ramified in group PA3 compared to those in group A3. OX-42 stained microglia were atrophied and become more ramified in group PA3 compared to those in group A3. Otherwise, p-ERK stained increased in group PA3 compared to those in group A3. These results indicate spianl microglial, astrocytic and ERK activation was decreased by intrathecal daily administration of propentofylline in existing antihyperalgia and allodynia paradigms (P<0.05 , P<0.01 ) .Conclusions Propentofylline intrathecal injection could generate antinociceptive, antihyperalgia and antiallodynic effect on a rat model of bone cancer pain. Moreover, the antinociceptive, antihyperalgic and antiallodynic effect of PPF intrathecal were generated by restrainting the activation of spinal astrocytes ,microglia and p-ERK.
目的探讨腹水传代与体外培养Walker-256细胞接种建立SD大鼠骨癌痛模型的可行性,并从多方面验证其稳定性与可靠性。方法体外培养与大鼠腹水传代增殖Walker-256细胞,种植于SD大鼠左胫骨上端。大鼠均分为Hank液对照组(NI组);热杀死肿瘤细胞(K1组);体外培养的肿瘤细胞种植组(V1组);腹水肿瘤细胞种植组(A1组),每组8只。通过疼痛行为学、镇痛药理学、影像学、病理组织学等评估肿瘤及疼痛发生发展情况。结果大鼠接种后肛温无明显变化。A1组与V1组术后第6天开始左侧后肢活动度开始下降,X摄片可见左胫骨上端骨小梁小缺损;第12天X摄片示骨皮质有破坏,SPECT可见接种区反应性骨形成活跃:第15天增重开始减缓:第18天X摄片显示大片骨质缺损,软组织肿块形成,左胫骨病理切片示骨癌细胞生长。大鼠接种后第6天到第18天,机械性压爪缩爪阈值、von Frey值进行性下降(P＜0.01),双下肢负重差进行性增高(P＜0.01)。术后第15天注射吗啡后模型大鼠机械性压爪缩爪阈值呈剂量依赖性增高,而纳洛酮可拮抗此效应。结论经腹水传代与体外培养Walker 256细胞均可用于SD大鼠骨癌痛模型的建立;经腹水传代建模更为简便:细胞接种后第6-18天产生进行性增高的机械性痛觉过敏与痛觉超敏,而热痛觉过敏相对较轻;该模型适宜于骨癌痛机制及镇痛药理学的研究。
第二部分骨癌痛大鼠脊髓胶质细胞及其表达的变化
研究证实神经损伤与组织炎症时疼痛的产生与维持与脊髓胶质细胞激活有关。然而,在骨癌痛时脊髓胶质细胞的改变及其作用尚不清楚。目的了解雌性SD大鼠一侧胫骨注射同系Walker 256癌细胞后脊髓胶质细胞的变化,从而研究骨癌痛产生与维持的机制。方法应用大鼠体内腹水传代Walker 256乳腺癌细胞种植于一侧胫骨建立骨癌痛模型,雌性SD大鼠,体重为150-180g,随机均分为5组,每组5只:对照(N2)组、热杀死肿瘤细胞(K2)组、不同时间骨癌痛3组(A2-d6,A2-d12,A2-d18)。
结果骨癌痛大鼠L4～L6两侧脊髓星形胶质细胞与小胶质细胞显著增加并激活,表现为胶质纤维酸性蛋白(GFAP)和小胶质细胞标志物OX-42免疫组化染色显著增强,尤其以后角Ⅰ-Ⅱ层最为显著,围绕脊髓中央管附近(X层)也有显著着色,细胞明显增大,与N2组及K2组比较,差异均有统计学意义(P＜0.05,P＜0.01);其中GFAP染色术后第6-18天呈进行性增高,以A2-d18组最为显著,与A2-d6组比较,P＜0.01;OX-42染色术后第6-18天呈进行性降低,以A2-d6组最为显著(P＜0.05,P＜0.01)。
结论胫骨注射Walker 256肿瘤细胞后激活脊髓胶质细胞,这可能与自发痛行为、痛觉过敏及痛觉超敏有关。其次,星形胶质细胞与小胶质细胞在两侧脊髓灰质均有激活,可能反映了本模型骨癌痛特征中“镜像痛”的产生机制。脊髓小胶质细胞激活在骨癌痛产生中可能起主要作用,而星形胶质细胞激活在骨癌痛维持中可能起重要作用。
第三部分鞘内注射丙戊茶碱对大鼠骨癌痛的镇痛与抗痛敏作用及其脊髓机理
目的探讨鞘内注射丙戊茶碱(PPF)对大鼠骨癌痛的镇痛、抗痛觉过敏与抗痛觉超敏作用,并通过脊髓胶质细胞、磷酸化细胞外信号调节蛋白激酶的变化研究其作用的脊髓部位机理。方法40只SD大鼠以随机数字法均分为4组,每组10只:对照组(N3)、PPF组(P3)、左胫骨癌细胞种植组(A3)、左胫骨癌细胞种植+鞘内PPF治疗组(PA3)。手术后第9-12天每日1次鞘内分别注射生理盐水μl、PPF 10μg或生理盐水10μl。给药前后分别行von Frey值测定,术后第12天鞘内注药4小时后,分别行脊髓免疫组化染色及Western blot分析。结果与A3组比较,PA3组鞘内注射PPF后3h、4h、5h机械性痛阈值明显增高(P＜0.01);术后第9-12天PA3组每日鞘内注射PPF后,机械性痛阈值均有显著增高(P＜0.01)。与A3组相比,PA3组星形胶质细胞数量减少,胞体减小,染色变浅,突起减少(P＜0.05,P＜0.01);PA3组小胶质细胞胞体减小,数量减少,染色变浅,突起增多(P＜0.05,P＜0.01);PA3组p-ERK颗粒明显减少,染色变浅,颗粒变小(P＜0.05,P＜0.01)。结论鞘内注射PPF10μg对大鼠骨癌痛具有一定的镇痛、抗痛觉过敏与抗痛觉超敏作用;鞘内注射PPF通过抑制星形胶质细胞及小胶质细胞的激活,同时抑制脊髓背角ERK磷酸化而产生镇痛与抗痛敏作用。
Part I Study of A SD Rat Model of Bone Cancer Pain Created by Using Walker 256 Cultured in Vitro or in Vivo
Objective To investigate the possibility and verify the reliability of a SD rat model of bone cancer pain using Walker 256 cultivate in Vitro or in Vivo. Methods Bone cancer pain model was created by receiving left superior extremity intra-tibial inoculations of Walker 256 syngeneic SD rat carcinoma cells which culture and proliferation in vitro(group V1) or in vivo to produce ascites (group A1) in female SD rats weighing 150-180g,n=8. Rat of group N1 or group K1 were inoculated of Hank's or heat-killed cells. The development of bone tumour and pain were observated by digital radiology, ECT, MRI, histology, pain behavioural signs indicative of pain and analgesic pharmacodynamics. Results Rats of four groups did not show changes in body weight during 18 days. Rats of group A and group V displayed decrease of left hint limb activity and minute defect of bone trabecula in the proximal epiphysis by radiological analysis by day 6; Further deterioration was detected at day 12 post-injection with full thickness unicortical bone loss by radiological analysis and bone formation active in region by SPECT; Rats of group A and group V displayed signs of weight loss by day 15. At the final time point, 18 days after the cells injection, full thickness bicortical bone loss and form soft tissue tumor were observed by X ray. Bones inoculated with live cells showed infiltration of bone marrow spaces by malignant tumor on day 18 after inoculation in histology. Rats of group A and group V displayed the gradual development reduced of PWT, von Frey threshold and weight bearing of left hind limb between day 6 and day 18(P <0.01) .Morphine (2-16 mg/kg, S.C.) produced a dose-dependent reduction and Naloxone antagonist manner in the response frequency of hind paw withdrawal to Mechanical stimulation on 15 day following intra-tibia inoculation. Conclusions These results suggested that SD rat model of bone cancer pain can be established by using Walker 256 Culture in Vitro or in Vivo , and the latter was more convenient; the gradual development of mechanical allodynia and mechanical hyperalgesia and reduced of weight bearing on the affected limb, beginning on day 6 following inoculation, whereas the thermal hyperalgesia was not significant; Behavioral data suggest a reasonable time window for study the mechanism of bone cancer pain and evaluation of antinociceptive agents between day 6 and 18 after walker 256 inoculations.
Part II Spinal Glia Cell Activation in The SD Rat Model of Bone Cancer Pain Produced by Walker 256 Cancer Cell Inoculation in Tibia
Investigations demonstrated that glial activation in the spinal cord are involved in the development and persistent of pain induced by nerve injury and tissue inflammation. However, the alteration and role of glial cells in spinal cord of bone cancer pain is not well understood. Objective This study explored the spinal glial alteration in a rat model of bone cancer pain produced by injecting syngeneic Walker 256 rat mammary gland Cancer cells into the unilateral tibia of female SD rats. Thereby desire to study the mechanism of development and persistent of bone cancer pain. Methods Bone cancer pain model was created by receiving left superior extremity intra-tibial inoculations of Walker 256 syngeneic SD rat carcinoma cells which culture and proliferation in vivo to produce ascites (A2) in 25 female SD rats weighing 150-180g. The rats were divided by 5 groups randomly which included group N2(control), group K2 (inoculated of heat-killed cells) and group A2, and group A2 was consisted of A2(d6), A2d(12) and A2d(18) groups depended on the day of post inoculation. Results The results showed that astrocytes and microglia were significantly enhanced and activated in the L4-L6 superficial spinal cord bilateralis in rats of inoculation of Walker cancer cells, characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker, P <0.05, P <0.01) and OX-42 (microglial marker,P <0.05, P <0.01). Spinal GFAP staining progression increase on day 6 to day 18 post cell inoculation, and it was prominent on day of 18 postoperation (P <0.05, P <0.01). While Spinal OX-42 staining progression decrease on day 6 to day 18 post cell inoculation, and it was distinguished on day 6 post inoculation (P <0.05, P <0.01). Conclusions These results demonstrate that injection of Walker 256 cancer cells into the tibia activates the spinal glial cells, which may contribute to hyperalgesia and allodynia. Furthermore, the astrocytes and microglia activated in ipsi- and Contralateral superficial dorsal horns highlights the possible involvement in the mirror imaging pain phenomenon in neuroethology of this model of bone cancer pain.
Part III Anti-nociceptive and Anti-hyperalgesic Effect of Intrathecal Propentofylline on A Rat Model of Bone Cancer Pain and Its Mechanism in Spinal Cord
Objective The present study was undertaken to determine whether intrathecal injection propentofylline, a glial modulating agent, could generate anti-nociceptive, anti-hyperalgesic and anti-allodynic effect on a rat model of bone cancer pain. Moreover, investigate its effective mechanism through the alteration of spinal glial and p-ERK in spinal cord. Methods 40 SD rats were divided by 4 groups(n=10) randomly which included group N3(control), group P3 (intrathecal injection PPF 10μg), group A3(model of bone cancer pain and 0.9%NS intrathecal injection), and group PA3 (model of bone cancer pain and PPF 10μg intrathecal injection). Propentofylline or 0.9% was administered daily intrathecally during 9-12 day postoperation. Determination of von Frey threshold before and after intrathecal administered. Spinal cords (L4-L6 segments) were removed for immunohistochemical stainning and Western blot analysis 4h after intrathecal injection on day 12 post operation. Results The von Frey threshold in group PA3 was increased obviously during 3-5 h post PPF intrathecal injection compare to that in group A3 (P <0.01) , and the pain threshold was increased after PPF i.t. daily during 9-12d post inoculation. GFAP stained astrocyte were atrophied and become less ramified in group PA3 compared to those in group A3. OX-42 stained microglia were atrophied and become more ramified in group PA3 compared to those in group A3. Otherwise, p-ERK stained increased in group PA3 compared to those in group A3. These results indicate spianl microglial, astrocytic and ERK activation was decreased by intrathecal daily administration of propentofylline in existing antihyperalgia and allodynia paradigms (P<0.05 , P<0.01 ) .Conclusions Propentofylline intrathecal injection could generate antinociceptive, antihyperalgia and antiallodynic effect on a rat model of bone cancer pain. Moreover, the antinociceptive, antihyperalgic and antiallodynic effect of PPF intrathecal were generated by restrainting the activation of spinal astrocytes ,microglia and p-ERK.
引文
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