Endogenous opioids inhibit early-stage pancreatic pain in a mouse model of pancreatic cancer
Endogenous opioids inhibit early-stage pancreatic pain in a mouse model of pancreatic cancer
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DOI：
10.1053/j.gastro.2006.06.021
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发表时间：
2006-09-01
期刊：
影响因子：
29.4
通讯作者：
Mantyh, Patrick W.
中科院分区：
文献类型：
--
作者：
Sevcik, Molly A.;Jonas, Beth M.;Mantyh, Patrick W.
背景与目的：内源性阿片系统参与调节疼痛体验、应激反应和镇痛治疗的作用。最近的人体影像学研究表明，内脏疼痛有显著的强直性调节，这就提出了内源性阿片类药物是否能强直性调节内脏癌疼痛的问题。方法：采用在大鼠弹性酶-1启动子控制下，表达猿猴病毒40大T抗原前127个氨基酸的转基因小鼠，研究内源性阿片样物质在胰腺癌疼痛调节中的作用。内脏疼痛行为以驼背和发声的程度来评估。结果：虽然晚期胰腺癌小鼠表现出自发的、吗啡可逆的、内脏疼痛相关的行为，如驼背和发声，但这些行为在早期胰腺癌小鼠中不存在。在全身给予中枢神经系统（CNS）渗透性阿片受体拮抗剂纳洛酮或纳曲酮后，早期胰腺癌小鼠表现出明显的内脏疼痛相关行为，而全身给予中枢神经系统（CNS）非渗透性阿片受体拮抗剂纳洛酮-甲氧基胺并未诱导内脏疼痛行为的增加。结论：我们的研究结果表明中枢神经系统阿片类药物依赖机制强直性调节早期和晚期胰腺癌疼痛。了解在早期疾病中掩盖这种疼痛和在晚期疾病中驱动这种疼痛的机制可能有助于改善胰腺癌患者的诊断、治疗和护理。
Background & Aims: The endogenous opioid system is involved in modulating the experience of pain, the response to stress, and the action of analgesic therapies. Recent human imaging studies have shown a significant tonic modulation of visceral pain, raising the question of whether endogenous opioids tonically modulate the pain of visceral cancer. Methods: Transgenic mice expressing the first 127 amino acids of simian virus 40 large T antigen, under the control of the rat elastase-1 promoter, that spontaneously develop pancreatic cancer were used to investigate the role of endogenous opioids in the modulation of pancreatic cancer pain. Visceral pain behaviors were assessed as degree of hunching and vocalization. Results: Although mice with late-stage pancreatic cancer displayed spontaneous, morphine-reversible, visceral pain-related behaviors such as hunching and vocalization, these behaviors were absent in mice with early-stage pancreatic cancer. After systemic administration of the central nervous system (CNS)-penetrant opioid receptor antagonists naloxone or naltrexone, mice with early-stage pancreatic cancer displayed significant visceral pain-related behaviors, whereas systemic administration of the CNS-non-penetrant opioid antagonist naloxone-methiodide did not induce an increase in visceral pain behaviors. Conclusions: Our findings suggest that a CNS opioid-dependent mechanism tonically modulates early and late-stage pancreatic cancer pain. Understanding the mechanisms that mask this pain in early stage disease and drive this pain in late-stage disease may allow improved diagnosis, treatment, and care of patients with pancreatic cancer.