Clarification of mechanisms underlying the disability of morphine tolerance and dependence in the appropriate medication of morphine in palliative care of cancer pain

阐明在癌症疼痛姑息治疗中适当使用吗啡药物导致吗啡耐受和依赖性丧失的机制

基本信息

批准号：
10672152
负责人：
TAKAHASHI Masakatsu
金额：
$ 0.58万
依托单位：
NAGASAKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

In contrast to previous reports that repeated treatment with morphine rapidly develops tolerance to its analgesic effect, recent clinical findings have shown that morphine did not develop tolerance when used for the palliative of cancer pain. To elucidate such discrepancies, development of tolerance to morphine and U-50,488H, μ- and κ-opioid receptor agonists, respectively, given daily subcutaneously (s.c.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.), and, DPDPE, a selective δ-opioid receptor agonist given i.c.v. and i.t., was investigated by both tail-pinch (TP) method for phasic pain and formalin (FL) test for persistent pain stimulation, from the view of differences in pain types between cancer pain and phasic pain stimulation in the test screening for analgesics.Daily injection of morphine as well as U-50,488H resulted in the gradual loss of analgesic effect, indicating the development of tolerance to the effect in the TP test by any route of administration; however … More , in the FL test, both compounds given s.c. and i.c.v. did not develop tolerance whereas tolerance developed by i.t. administration, supporting above hypothesis that tolerance to analgesic effect of morphine against tonic pain such as cancer pain would be hard to develop. On the other hand, DPDPE given i.c.v. and i.t. easily developed tolerance in both tests. Thus, common mechanisms possibly underlie in the development of tolerance to the suppression of tonic pain by these μ- and κ-opioid receptor agonists, and advantageous clinical use of μ- and κ-agonists but not δ-opioid type is proposed. Additionally, both supraspinal and spinal sites are likely to participate in the development of tolerance to these opioids in the phasic pain, whereas supraspinal site is rather important for the disability of development of tolerance to the suppressive effect of morphine and U-50,488H on the tonic pain stimulation. An anxiolytic drug diazepam also suppressed formalin pain responses. The clinical findings that emotional factors such as anxiety, fear and despair play roles in the production and intensities of chronic pain, are therefore, firstly evidenced by this animal experiment. Less

与以前的报道相反，对吗啡的重复治疗迅速增强了其镇痛作用的耐受性，最近的临床发现表明，当用于姑息治疗癌症疼痛时，吗啡没有产生耐受性。为了阐明这种差异，分别对吗啡的耐受性和U-50,488H，μ-和κ阿片受体的发展，每天均一（s.c.）给予（s.c.），室内室内（i.c.v.）或静脉内（i.t.）和dpdpe，dpdpe，i.c.v.从两种尾刺（TP）方法研究的情况下，从癌症疼痛和疼痛刺激之间的疼痛类型之间的差异来研究，对镇痛学的测试筛查中的疼痛类型差异，对镇痛学的测试筛查中的疼痛类型差异。管理；但是……更多，在FL测试中，两种化合物给定的S.C.和I.C.V.没有发展耐受性，而I.T.产生的耐受性给药，支持上述假设，即吗啡对诸如癌症疼痛之类的补品疼痛的镇痛作用的耐受性很难发展。另一方面，dpdpe给定I.C.V.和I.T.在这两个测试中都很容易发展耐受性。这是在这些μ和κ阿片受体激动剂抑制补品疼痛的耐受性的基础上的基础，并提出了有利于μ-和κ-激动剂的临床使用，但提出了Δ-阿片类型类型的有利临床使用。此外，脊柱上和脊柱部位都可能参与对这些阿片类药物的耐受性的发展，而脊柱上的部位对于形成耐受性的耐受性和U-50,488H抑制作用的耐受性的残疾非常重要。抗焦虑药地西ep还抑制了福尔马林疼痛反应。因此，该动物实验首先证明了诸如焦虑，恐惧和绝望之类的情绪因素在生产和慢性疼痛的强度中扮演角色。较少的