神经病理性疼痛大鼠大麻素Ⅱ型受体介导的抗伤害作用及受体表达的研究
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摘要
[背景]神经病理性疼痛(Neuropathic Pain)是由于神经系统的原发损伤或功能障碍而引起的疼痛。目前发病机制不清，药物治疗效果不佳，缺乏有效的治疗措施，是困扰临床的一个挑战性课题。造成这种结局的一个重要原因是治疗神经病理性疼痛的药物的副作用尤其是其中枢神经系统副作用限制了药物的剂量，从而不能达到有效的镇痛和治疗作用。因而，探寻神经病理性疼痛的发病机制，寻求作用于脊髓或外周部位、不具有中枢神经系统副作用的药物，显得尤为迫切。CB2大麻素受体主要表达于外周免疫细胞，有研究表明CB2受体选择性激动剂能够抑制急性、炎性疼痛而不产生中枢神经系统副作用，但对于其在神经病理性疼痛中的作用研究较少，同时对于CB2受体是否表达于脊髓和背根神经节(DRG)，存在不同的报道，这些均需进一步验证。
[目的]观察选择性CB2受体激动剂AM1241对神经病理性疼痛的效果；并检测神经病理性疼痛形成过程中脊髓背角、DRG部位CB2受体表达的变化，探讨其治疗作用的分子机制。
[方法]第一部分雄性S-D大鼠36只，随机分为6组(n=6)：①CCI+安慰剂组，坐骨神经慢性紧缩模型(CCI)建立后10天(下同)，腹腔注射安慰剂；②CCI+AM1241低剂量组，腹腔注射AM1241，剂量为100μg／kg；③CCI+AM1241中剂量组，AM1241剂量为300μg／kg；④CCI+AM1241高剂量组，AM1241剂量为1000μg／kg；⑤CCI+AM1241高剂量+AM630组，腹腔注射AM1241和选择性CB2受体拮抗剂AM630，剂量分别为1000μg／kg和300μg／kg；⑥CCI+AM1241高剂量+AM251组，腹腔注射AM1241和选择性CB1受体拮抗剂AM251，剂量分别为1000μg／kg和300μg／kg。CCI模型采用慢性坐骨神经结扎的方法建立。坐骨神经结扎前后以及药物治疗前后，分别用von Frey纤毛刺激针测量机械性痛阈。
第二部分雄性S-D大鼠42只，随机分为7组(n=6)：①Con组，对照组；②S3组，假手术术后3天组；③C3组，CCI术后3天组；④S7组，假手术术后7天组；⑤C7组，CCI术后7天组；⑥S14组，假手术术后14天组；⑦C14组，CCI术后14天组。CCI模型采用慢性坐骨神经结扎的方法建立，假手术组仅显露坐骨神经，并不进行结扎。用von Frey纤毛刺激针测量各组大鼠机械性痛阈后处死大鼠，取手术侧腰膨大脊髓背角和L4、L5背根神经节标本，采用免疫蛋白印迹技术，从蛋白质水平研究神经病理性疼痛形成过程中CB2受体表达的变化。
[结果] CCI导致手术侧后爪的机械痛阈阈值降低(P＜0.05)；AM1241剂量依赖性地抑制CCI引起的机械异常痛敏(P＜0.05)；AM1241的作用可完全为选择性CB2受体拮抗剂AM630所阻断(P＜0.05)，而不受选择性CB1受体拮抗剂AM251的影响(P＞0.05)。各组大鼠脊髓和背根神经节部位均有CB2受体的表达；与对照组相比，CCI后7天、14天组脊髓背角CB2受体均发生上调(P＜0.05)，CCI后3天、7天、14天组背根神经节CB2受体均发生上调(P＜0.05)，CCI后3天脊髓背角、假手术各组脊髓背角和DRG部位CB2受体没有明显的变化(P＞0.05)。
[结论] AM1241可缓解由于慢性坐骨神经紧缩(CCI)导致的机械异常痛敏，且该作用是通过CB2受体介导的；神经病理性疼痛可导致脊髓背角和DRG部位的CB2受体发生上调，表明了脊髓和DRG也可能是CB2受体激动剂作用的靶点。
The CB2 cannabinoid receptor-mediated antinociception and its expression in rats with neuropathic pain
Background: Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. The mechanism underlying neuropathic pain is not clear and the pain often responds poorly to medical therapy. This may be due, in part, to adverse side effects of available medications that limit drug dosage. So it is needed to investigate the mechanism and explore drugs acting upon spinal cord or periphery without CNS side effects. CB2 cannabinoid receptors are expressed mainly on peripheral immune cells. It is suggested that selective CB2 agonists inhibit acute, inflammatory pain without producing CNS side effects. But study concerning their effects on neuropathic pain is scarce. In addition, reports on whether CB2 receptors are expressed on spinal cord and dorsal root ganglion are conflicting, making further investigation necessary.
Objectives: To investigate the effects of selective CB2 receptor agonist AM1241 on neuropathic pain models; To investigate changes of CB2 receptor expression in the spinal cord and DRG during the development of neuropathic pain; To explore the molecular mechanisms by which selective CB2 receptor agonists are effective in neuropathic pain.
Methods: Part one: Thirty-six male Sprague-Dawley rats were randomly divided into six groups(n=6):①CCI+ placebo, chronic constriction injury of the common sciatic nerve was performed on the rats, ten days later(the same as follows), placebo was administered peritoneally;②CCI+AM1241 (100μg/kg), the selective CB2 receptor agonist AM1241 was administered with a dose of 100μg/kg;③CCI+AM1241 (3001μg/kg);④CCI+AM1241 (1000μg/kg);⑤CCI+AM1241+AM630, AM1241 (1000μg/kg) and selective CB2 receptor antagonist AM630 (300μg/kg) were administered;⑥CCI+AM1241+AM251, AM1241 (1000μg/kg) and selective CB1 receptor antagonist AM251 (300μg/kg) were administered. CCI was performed by loosely tying the common sciatic nerve. Prior to and post-CCI and drug therapy, tactile withdrawal threshold was measured in the ipsilateral hind paw by using von Frey filaments.
Part two: Forty-two male Sprague-Dawley rats were divided into seven groups(n=6):①C group, control group;②S3 group, 3 days after sham operation;③C3 group, 3 days after CCI procedure;④S7 group, 7 days after sham operation;⑤C7 group, 7 days after CCI procedure;⑥S14 group, 14 days after sham operation;⑦C14 group, 14 days after CCI procedure. CCI was performed by loosely tying the common sciatic nerve. The sham groups received the same procedure except for nerve ligation. After the tactile withdrawal threshold was measured with von Frey filaments, rats were killed at scheduled time and the ipsilateral spinal dorsal hom and DRG were harvested. Western blot analysis was used to investigate the changes of CB2 receptor expression in the spinal cord and DRG during development of neuropathic pain.
Results: CCI induced a decrease in the tactile withdrawal threshold in the ipsilateral hind paw. AM1241 produced a dose-dependent inhibition of CCI-induced tactile allodynia in rats. The effect of AM1241 was completely blocked by the CB2 receptor-selective antagonist AM630 but was not affected by the CB1 receptor-selective antagonist AM251. CB2 receptor was expressed in the spinal cord and DRG of all groups. Compared with that of the control group, CB2 receptor expression was up-regulated in the ipsilateral spinal dorsal horn and DRG for the C7, C14 and C3, C7, C14 group, respectively. There were no significant changes in the CB2 receptor expression in the spinal dorsal hom and DRG for all sham groups.
Conclusion: The selective CB2 receptor agonist AM1241 could alleviate CCI-induced tactile allodynia in a CB2-mediated manner. Neuropathic pain states could induce an up-regulation of the CB2 receptor expression in the spinal dorsal hom and DRG, suggesting that spinal cord and DRG might be the targets for CB2 receptor agonist.
[目的]观察选择性CB2受体激动剂AM1241对神经病理性疼痛的效果；并检测神经病理性疼痛形成过程中脊髓背角、DRG部位CB2受体表达的变化，探讨其治疗作用的分子机制。
[方法]第一部分雄性S-D大鼠36只，随机分为6组(n=6)：①CCI+安慰剂组，坐骨神经慢性紧缩模型(CCI)建立后10天(下同)，腹腔注射安慰剂；②CCI+AM1241低剂量组，腹腔注射AM1241，剂量为100μg／kg；③CCI+AM1241中剂量组，AM1241剂量为300μg／kg；④CCI+AM1241高剂量组，AM1241剂量为1000μg／kg；⑤CCI+AM1241高剂量+AM630组，腹腔注射AM1241和选择性CB2受体拮抗剂AM630，剂量分别为1000μg／kg和300μg／kg；⑥CCI+AM1241高剂量+AM251组，腹腔注射AM1241和选择性CB1受体拮抗剂AM251，剂量分别为1000μg／kg和300μg／kg。CCI模型采用慢性坐骨神经结扎的方法建立。坐骨神经结扎前后以及药物治疗前后，分别用von Frey纤毛刺激针测量机械性痛阈。
第二部分雄性S-D大鼠42只，随机分为7组(n=6)：①Con组，对照组；②S3组，假手术术后3天组；③C3组，CCI术后3天组；④S7组，假手术术后7天组；⑤C7组，CCI术后7天组；⑥S14组，假手术术后14天组；⑦C14组，CCI术后14天组。CCI模型采用慢性坐骨神经结扎的方法建立，假手术组仅显露坐骨神经，并不进行结扎。用von Frey纤毛刺激针测量各组大鼠机械性痛阈后处死大鼠，取手术侧腰膨大脊髓背角和L4、L5背根神经节标本，采用免疫蛋白印迹技术，从蛋白质水平研究神经病理性疼痛形成过程中CB2受体表达的变化。
[结果] CCI导致手术侧后爪的机械痛阈阈值降低(P＜0.05)；AM1241剂量依赖性地抑制CCI引起的机械异常痛敏(P＜0.05)；AM1241的作用可完全为选择性CB2受体拮抗剂AM630所阻断(P＜0.05)，而不受选择性CB1受体拮抗剂AM251的影响(P＞0.05)。各组大鼠脊髓和背根神经节部位均有CB2受体的表达；与对照组相比，CCI后7天、14天组脊髓背角CB2受体均发生上调(P＜0.05)，CCI后3天、7天、14天组背根神经节CB2受体均发生上调(P＜0.05)，CCI后3天脊髓背角、假手术各组脊髓背角和DRG部位CB2受体没有明显的变化(P＞0.05)。
[结论] AM1241可缓解由于慢性坐骨神经紧缩(CCI)导致的机械异常痛敏，且该作用是通过CB2受体介导的；神经病理性疼痛可导致脊髓背角和DRG部位的CB2受体发生上调，表明了脊髓和DRG也可能是CB2受体激动剂作用的靶点。
The CB2 cannabinoid receptor-mediated antinociception and its expression in rats with neuropathic pain
Background: Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. The mechanism underlying neuropathic pain is not clear and the pain often responds poorly to medical therapy. This may be due, in part, to adverse side effects of available medications that limit drug dosage. So it is needed to investigate the mechanism and explore drugs acting upon spinal cord or periphery without CNS side effects. CB2 cannabinoid receptors are expressed mainly on peripheral immune cells. It is suggested that selective CB2 agonists inhibit acute, inflammatory pain without producing CNS side effects. But study concerning their effects on neuropathic pain is scarce. In addition, reports on whether CB2 receptors are expressed on spinal cord and dorsal root ganglion are conflicting, making further investigation necessary.
Objectives: To investigate the effects of selective CB2 receptor agonist AM1241 on neuropathic pain models; To investigate changes of CB2 receptor expression in the spinal cord and DRG during the development of neuropathic pain; To explore the molecular mechanisms by which selective CB2 receptor agonists are effective in neuropathic pain.
Methods: Part one: Thirty-six male Sprague-Dawley rats were randomly divided into six groups(n=6):①CCI+ placebo, chronic constriction injury of the common sciatic nerve was performed on the rats, ten days later(the same as follows), placebo was administered peritoneally;②CCI+AM1241 (100μg/kg), the selective CB2 receptor agonist AM1241 was administered with a dose of 100μg/kg;③CCI+AM1241 (3001μg/kg);④CCI+AM1241 (1000μg/kg);⑤CCI+AM1241+AM630, AM1241 (1000μg/kg) and selective CB2 receptor antagonist AM630 (300μg/kg) were administered;⑥CCI+AM1241+AM251, AM1241 (1000μg/kg) and selective CB1 receptor antagonist AM251 (300μg/kg) were administered. CCI was performed by loosely tying the common sciatic nerve. Prior to and post-CCI and drug therapy, tactile withdrawal threshold was measured in the ipsilateral hind paw by using von Frey filaments.
Part two: Forty-two male Sprague-Dawley rats were divided into seven groups(n=6):①C group, control group;②S3 group, 3 days after sham operation;③C3 group, 3 days after CCI procedure;④S7 group, 7 days after sham operation;⑤C7 group, 7 days after CCI procedure;⑥S14 group, 14 days after sham operation;⑦C14 group, 14 days after CCI procedure. CCI was performed by loosely tying the common sciatic nerve. The sham groups received the same procedure except for nerve ligation. After the tactile withdrawal threshold was measured with von Frey filaments, rats were killed at scheduled time and the ipsilateral spinal dorsal hom and DRG were harvested. Western blot analysis was used to investigate the changes of CB2 receptor expression in the spinal cord and DRG during development of neuropathic pain.
Results: CCI induced a decrease in the tactile withdrawal threshold in the ipsilateral hind paw. AM1241 produced a dose-dependent inhibition of CCI-induced tactile allodynia in rats. The effect of AM1241 was completely blocked by the CB2 receptor-selective antagonist AM630 but was not affected by the CB1 receptor-selective antagonist AM251. CB2 receptor was expressed in the spinal cord and DRG of all groups. Compared with that of the control group, CB2 receptor expression was up-regulated in the ipsilateral spinal dorsal horn and DRG for the C7, C14 and C3, C7, C14 group, respectively. There were no significant changes in the CB2 receptor expression in the spinal dorsal hom and DRG for all sham groups.
Conclusion: The selective CB2 receptor agonist AM1241 could alleviate CCI-induced tactile allodynia in a CB2-mediated manner. Neuropathic pain states could induce an up-regulation of the CB2 receptor expression in the spinal dorsal hom and DRG, suggesting that spinal cord and DRG might be the targets for CB2 receptor agonist.
引文
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