GABA_B受体介导大鼠胫骨癌痛及其脊髓机制
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摘要
第一部分:鞘内注射巴氯芬及CGP35348对胫骨癌痛大鼠机械痛敏的影响
目的观察胫骨癌痛大鼠鞘内注射γ-氨基丁酸B型(γ-aminobutyric acid B receptor, GABAB)受体特异性激动剂巴氯芬及拮抗剂CGP35348对左后肢机械缩足阈值(mechanical withdrawal threshold , MWT)的影响。
方法将Walker 256乳腺癌细胞注入雌性未孕SD大鼠左后肢胫骨髓腔建立胫骨癌痛模型,术后每2天使用Von Frey纤维测MWT一次,时间选择在上午9:00-10:00进行。造模后第3天蛛网膜下腔置管。于第9天将造模成功的32只大鼠随机分为4组(n = 8)即N1组(生理盐水,10μl )、B1组(巴氯芬,0.1μg)、C1组(CGP35348 60μg)、D1组(CGP35348 60μg +巴氯芬0.1μg),均为单次注药。造模前1 d(t0)、给药前0.5 h(t1)、给药后0.5(t2)、1、2、4、8、24 h使用Von Frey纤维测定左后肢MWT。
结果造模后第9天,t1与t0比较MWT明显下降(P <0.01);B1组大鼠在注药后0.5 h MWT达峰值、4 h内阈值与N1组比较差别有统计学意义(P <0.01);C1、D1组大鼠与N1组比较MWT没有明显变化(P >0.05)。
结论(1)鞘内注射巴氯芬能减缓胫骨癌痛大鼠的机械痛敏;(2)单独使用CGP35348对大鼠胫骨癌痛没有明显影响;(3) CGP35348与巴氯芬合用可以明显抑制后者对胫骨癌痛的镇痛作用;(4) GABAB受体可能介导了胫骨癌痛的维持。
第二部分:鞘内注射巴氯芬及CGP35348对胫骨癌痛大鼠脊髓背角磷酸化细胞外信号调节激酶(p-ERK1/2)表达的影响
目的观察胫骨癌痛大鼠鞘内注射GABAB受体激动剂巴氯芬及拮抗剂CGP35348后对脊髓背角p-ERK1/2表达的影响,探讨GABAB受体介导大鼠胫骨癌痛的可能脊髓机制。
方法将Walker 256乳腺癌细胞注入雌性未孕SD大鼠胫骨髓腔建立胫骨癌痛模型,术后每2天使用Von Frey纤维测痛一次,时间选择在上午9:00-10:00进行。造模后第3天蛛网膜下腔置管。第9天将造模成功的32只大鼠随机分为4组(n = 8)即N2组(生理盐水, 10μl)、B2组(巴氯芬, 0.1μg)、C2组(CGP35348, 60μg)、D2组(CGP35348 60μg +巴氯芬0.1μg),连续4 d鞘内给药,每天一次,在最后一次给药6 h后分别处死大鼠,取L3-L5脊髓、冰冻切片、用免疫组织化学方法检测脊髓背角p-ERK1/2表达。
结果(1)给药后6 h B2组大鼠较N2组脊髓背角p-ERK1/2阳性细胞数(NUM)明显减少(P <0.05),积分光密度值(IOD)下降(P <0.05); (2) C2、D2组与N2组大鼠的NUM及IOD差别没有统计学意义(P>0.05)。
结论(1)鞘内注射巴氯芬可使胫骨癌痛大鼠脊髓背角p-ERK1/2表达减少;(2) CGP35348可以抑制巴氯芬导致的胫骨癌痛大鼠脊髓p-ERK1/2表达减少;(3) GABAB受体可能通过调控下游p-ERK1/2水平介导胫骨癌痛。
Part one: The effect of lntrathecal injection Baclofen and CGP35348 on mechanical hyperalgesia in tibia bone cancer pain rats .
Objective To observe the effect of left hind limb on mechanical withdrawal threshold(MWT)by intrathecal injection agonist Baclofen and antagonist CGP35348 ofγ-aminobutyric acid B(GABAB) receptor in tabia bone cancer pain rats .
Method We established rats model of tibia bone cancer by making Walker 256 breast carcinoma cells to inoculated into the left hind limb tibia medullaris cavity of the female unpregnancy SD rats. Use Von Frey fiber examine MWT every two days at 9:00-10:00. Set pipes into subarachnoid space of all rats after establishing model 3 d. Nine days after successfully model establishment, 32 SD rats was divided into experimental 4 groups (n=8) randomly including N1 group(NS, 10μl)、B1 group(Baclofen, 0.1μg)、C1 group(CGP35348, 60μg)、D1 group(CGP35348, 60μg +Baclofen, 0.1μg).The day before making model (t0)、0.5 h pre- (t1) and 0.5(t2)、1、2、4、8、24 h post-dosage , MWT of the left posterior limb was record.
Result After estalishing model 9 d, significant increase of the MWT was recognized comparing t1 with t0 (P<0.01).Comparing group B1 with group N1,reach peak in post dosage 0.5 h and persistent effect was achieved for 4 h post-dosage(P <0.01). But there were no significant difference of MWT with N1、C1 and D1 group (P>0.05) .
Conclusion (1) Intrathecal injection Baclofen has significantly analgesic effect in rats of tibia bone cancer pain model. (2) Signally use CGP35348 could not influence the tibia bone cancer pain. (3) Combining CGP35348 with Baclofen can be inhibited the anti-nociceptive effect of the latter. (4) GABAB receptor maybe mediate the maintenance of tibia bone cancer pain.
Part two: The effects of intrathecal injection Baclofen and CGP35348 on the expression of spinal cord dorsal horn p-ERK1/2 in rats model of tibia bone cancer pain
Objective To observe the effect of p-ERK1/2 expression in tibia bone cancer pain rats by intrathecal injection agonist Baclofen and antagonist CGP35348 of GABAB receptor and approach the spinal possible mechanism of GABAB receptor mediating tibia bone cancer pain.
Methods We established rat model of bone cancer by using Walker256 breast carcinoma cells which was inoculated into the tibia medullaris cavity of the female unpregnancy SD rats. Use Von Frey fiber examine pain every two days at 9:00-10:00. Set pipes into subarachnoid space of all rats after establishing model 3 d. Nine days after successfully model establishment, 32 SD rats was divided into experimental 4 groups (n = 8) including N2 group(NS , 10μl)、B2 group(Baclofen, 0.1μg)、C2 group(CGP35348, 60μg)、D2 group(CGP35348 60μg + Baclofen 0.1μg). The 4 days continues and regular dosage was administrated , one times per day. 6 h after the last dosage, all the rats were killed and took out of L3-L5 spinal cord with frozen section for p-ERK1/2 immunohistochemical test respectively.
Results (1) In lumbar spinal cord significant decrease of the p-ERK1/2 positive cells(NUM) and integral optical density(IOD) was found between group B2 with group N2(P<0.05). (2) There were no significant difference of NUM and IOD with N2、C2 and D2 group (P>0.05).
Conclusion (1) The p-ERK1/2 expresstion of spinal cord droal horn were reduced by intrathecal injection Baclofen in tibia bone cancer pain rats. (2) The reduction of p-ERK1/2 expression by Baclofen can be blocked by CGP35348. (3) The GABAB receptor may through control downstream p-ERK1/2 to mediate tibia bone cancer pain .
目的观察胫骨癌痛大鼠鞘内注射γ-氨基丁酸B型(γ-aminobutyric acid B receptor, GABAB)受体特异性激动剂巴氯芬及拮抗剂CGP35348对左后肢机械缩足阈值(mechanical withdrawal threshold , MWT)的影响。
方法将Walker 256乳腺癌细胞注入雌性未孕SD大鼠左后肢胫骨髓腔建立胫骨癌痛模型,术后每2天使用Von Frey纤维测MWT一次,时间选择在上午9:00-10:00进行。造模后第3天蛛网膜下腔置管。于第9天将造模成功的32只大鼠随机分为4组(n = 8)即N1组(生理盐水,10μl )、B1组(巴氯芬,0.1μg)、C1组(CGP35348 60μg)、D1组(CGP35348 60μg +巴氯芬0.1μg),均为单次注药。造模前1 d(t0)、给药前0.5 h(t1)、给药后0.5(t2)、1、2、4、8、24 h使用Von Frey纤维测定左后肢MWT。
结果造模后第9天,t1与t0比较MWT明显下降(P <0.01);B1组大鼠在注药后0.5 h MWT达峰值、4 h内阈值与N1组比较差别有统计学意义(P <0.01);C1、D1组大鼠与N1组比较MWT没有明显变化(P >0.05)。
结论(1)鞘内注射巴氯芬能减缓胫骨癌痛大鼠的机械痛敏;(2)单独使用CGP35348对大鼠胫骨癌痛没有明显影响;(3) CGP35348与巴氯芬合用可以明显抑制后者对胫骨癌痛的镇痛作用;(4) GABAB受体可能介导了胫骨癌痛的维持。
第二部分:鞘内注射巴氯芬及CGP35348对胫骨癌痛大鼠脊髓背角磷酸化细胞外信号调节激酶(p-ERK1/2)表达的影响
目的观察胫骨癌痛大鼠鞘内注射GABAB受体激动剂巴氯芬及拮抗剂CGP35348后对脊髓背角p-ERK1/2表达的影响,探讨GABAB受体介导大鼠胫骨癌痛的可能脊髓机制。
方法将Walker 256乳腺癌细胞注入雌性未孕SD大鼠胫骨髓腔建立胫骨癌痛模型,术后每2天使用Von Frey纤维测痛一次,时间选择在上午9:00-10:00进行。造模后第3天蛛网膜下腔置管。第9天将造模成功的32只大鼠随机分为4组(n = 8)即N2组(生理盐水, 10μl)、B2组(巴氯芬, 0.1μg)、C2组(CGP35348, 60μg)、D2组(CGP35348 60μg +巴氯芬0.1μg),连续4 d鞘内给药,每天一次,在最后一次给药6 h后分别处死大鼠,取L3-L5脊髓、冰冻切片、用免疫组织化学方法检测脊髓背角p-ERK1/2表达。
结果(1)给药后6 h B2组大鼠较N2组脊髓背角p-ERK1/2阳性细胞数(NUM)明显减少(P <0.05),积分光密度值(IOD)下降(P <0.05); (2) C2、D2组与N2组大鼠的NUM及IOD差别没有统计学意义(P>0.05)。
结论(1)鞘内注射巴氯芬可使胫骨癌痛大鼠脊髓背角p-ERK1/2表达减少;(2) CGP35348可以抑制巴氯芬导致的胫骨癌痛大鼠脊髓p-ERK1/2表达减少;(3) GABAB受体可能通过调控下游p-ERK1/2水平介导胫骨癌痛。
Part one: The effect of lntrathecal injection Baclofen and CGP35348 on mechanical hyperalgesia in tibia bone cancer pain rats .
Objective To observe the effect of left hind limb on mechanical withdrawal threshold(MWT)by intrathecal injection agonist Baclofen and antagonist CGP35348 ofγ-aminobutyric acid B(GABAB) receptor in tabia bone cancer pain rats .
Method We established rats model of tibia bone cancer by making Walker 256 breast carcinoma cells to inoculated into the left hind limb tibia medullaris cavity of the female unpregnancy SD rats. Use Von Frey fiber examine MWT every two days at 9:00-10:00. Set pipes into subarachnoid space of all rats after establishing model 3 d. Nine days after successfully model establishment, 32 SD rats was divided into experimental 4 groups (n=8) randomly including N1 group(NS, 10μl)、B1 group(Baclofen, 0.1μg)、C1 group(CGP35348, 60μg)、D1 group(CGP35348, 60μg +Baclofen, 0.1μg).The day before making model (t0)、0.5 h pre- (t1) and 0.5(t2)、1、2、4、8、24 h post-dosage , MWT of the left posterior limb was record.
Result After estalishing model 9 d, significant increase of the MWT was recognized comparing t1 with t0 (P<0.01).Comparing group B1 with group N1,reach peak in post dosage 0.5 h and persistent effect was achieved for 4 h post-dosage(P <0.01). But there were no significant difference of MWT with N1、C1 and D1 group (P>0.05) .
Conclusion (1) Intrathecal injection Baclofen has significantly analgesic effect in rats of tibia bone cancer pain model. (2) Signally use CGP35348 could not influence the tibia bone cancer pain. (3) Combining CGP35348 with Baclofen can be inhibited the anti-nociceptive effect of the latter. (4) GABAB receptor maybe mediate the maintenance of tibia bone cancer pain.
Part two: The effects of intrathecal injection Baclofen and CGP35348 on the expression of spinal cord dorsal horn p-ERK1/2 in rats model of tibia bone cancer pain
Objective To observe the effect of p-ERK1/2 expression in tibia bone cancer pain rats by intrathecal injection agonist Baclofen and antagonist CGP35348 of GABAB receptor and approach the spinal possible mechanism of GABAB receptor mediating tibia bone cancer pain.
Methods We established rat model of bone cancer by using Walker256 breast carcinoma cells which was inoculated into the tibia medullaris cavity of the female unpregnancy SD rats. Use Von Frey fiber examine pain every two days at 9:00-10:00. Set pipes into subarachnoid space of all rats after establishing model 3 d. Nine days after successfully model establishment, 32 SD rats was divided into experimental 4 groups (n = 8) including N2 group(NS , 10μl)、B2 group(Baclofen, 0.1μg)、C2 group(CGP35348, 60μg)、D2 group(CGP35348 60μg + Baclofen 0.1μg). The 4 days continues and regular dosage was administrated , one times per day. 6 h after the last dosage, all the rats were killed and took out of L3-L5 spinal cord with frozen section for p-ERK1/2 immunohistochemical test respectively.
Results (1) In lumbar spinal cord significant decrease of the p-ERK1/2 positive cells(NUM) and integral optical density(IOD) was found between group B2 with group N2(P<0.05). (2) There were no significant difference of NUM and IOD with N2、C2 and D2 group (P>0.05).
Conclusion (1) The p-ERK1/2 expresstion of spinal cord droal horn were reduced by intrathecal injection Baclofen in tibia bone cancer pain rats. (2) The reduction of p-ERK1/2 expression by Baclofen can be blocked by CGP35348. (3) The GABAB receptor may through control downstream p-ERK1/2 to mediate tibia bone cancer pain .
引文
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[2] Binet V, Le Corre L, Acher F, et al. The heptahelical domain of GABAB2 is activated directly by CGP7930,a positive allosteric modulator of the GABAB receptor[J]. J hem.,2004,279(28):29085-29091.
[3] Brusberg M , Ravnefjor A, Martinsson R, et al. The GABAB receptor agonist, baclofen, and the positive allosteric modulator,CGP7930,inhibit visceral pain - related responses to colorectal distension in rats[J]. Neuropharmacology, 2009, 56 (2): 362–367.
[4] Shafizadeh M, Semnanian S, Zarrindast MR, et al. Involvement of GABAB Receptors in the Antinociception Induced by Baclofen in the Formalin Test[J]. Gen. Pharmac,1997, 28(4):611-615.
[5] Malan TP, Mata HP, Porreca F, et al. Spinal GABAA and GABAB Receptor Pharmacology in a Rat Model of Neuropathic Pain[J]. Anesthesiology, 2002,96(5): 1161-1167.
[6] Andoh T, Sugiyama K, Fujita M, et al. Pharmacological Evaluation of Morphine and Non-opioid Analgesic Adjuvants in a Mouse Model of Skin Cancer Pain[J]. Biol. Pharm. Bull,2008,31(3): 520-522 .
[7] New DC, An H, Ip NY, et al. GABAB heterodimeric receptors promote Ca2+ influx via store-operated channels in rat cortical neurons and transfected Chinesehamsterovary cells[J]. Neuroscience,2006,137(4):1347-1358.
[8] Hirono M, Yoshioka T, Konishi S. GABAB receptor activation enhances mGluR- mediated responses at cerebellar excitatory synapses[J]. Nature Neurosci, 2001, 4(12):1207-1216.
[9] Tu HJ, Rondard P, Xu CJ, et al. Dominant role of GABAB2 and Gβγfor GABAB receptor-mediated-ERK1/2/CREB pathway in cerebellar neurons[J]. Cellular Signalling, 2007,19(9):1996–2002.
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[2] Sabino MC, Ghilardi JR, Feia KJ, et al. The involvement of prostaglandins in tumorigenesis, tumor-induced osteolysis and bone cancer pain [J]. J Musculoskelet Neuronal Interact,2002,2(6):561-562.
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