Modulation of acute morphine tolerance by corticotropin-releasing factor and dynorphin A in the mouse spinal cord.
Modulation of acute morphine tolerance by corticotropin-releasing factor and dynorphin A in the mouse spinal cord.
复制标题
促肾上腺皮质激素释放因子和强啡肽 A 对小鼠脊髓急性吗啡耐受的调节。
DOI：
10.1016/0024-3205(92)90003-8
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发表时间：
1992
期刊：
影响因子：
6.1
通讯作者：
Takemori,AE
中科院分区：
文献类型：
--
作者：
Song,SH;Takemori,AE
以前，我们已经证明，鞘内（i.t.）在小鼠中施用促肾上腺皮质激素释放因子（CRF）产生刺激特异性抗伤害感受和通过涉及脊髓κ阿片受体的机制调节吗啡诱导的抗伤害感受。最近，我们也发现CRF在体外灌流的小鼠脊髓中释放免疫反应性强啡肽A，一种假定的内源性κ阿片受体激动剂。强啡肽A侧脑室注射（i. c. v.）已经显示出对小鼠的吗啡耐受性的表达的调节。在本研究中，i.t.在急性耐受模型中研究了给予CRF和强啡肽A对吗啡耐受的影响。小鼠皮下注射100 mg/kg硫酸吗啡（MS）可引起对吗啡诱导的镇痛作用的急性耐受。MS的抗伤害性ED_（50）从4.4mg/kg（未处理小鼠）增加到17.9mg/kg（注射100 mg/kg MS后4 h）。为研究脊髓注射CRF和强啡肽A对吗啡耐受表达的调节作用，分别给大鼠腹腔注射CRF和强啡肽A。分别在15 min和5 min时，然后通过甩尾试验测试耐受小鼠。耐受小鼠经腹腔注射MS后，其镇痛ED_（50）分别降至8.8mg/kg和7.1mg/kg。给予CRF（0.1 nmol）和强啡肽A（0.2 nmol）。相反，当i.t.给药时，0.5 nmol α-螺旋CRF（9-41）（CRF拮抗剂）和0.4 nmol norbinaltorphimine（高选择性κ阿片受体拮抗剂），在耐受小鼠甩尾实验前15 min，MS的抗伤害ED_（50）分别为56.6 mg/kg和88.8 mg/kg。这些数据证实了强啡肽A对吗啡耐受的调节作用，并提示在中枢神经系统多个区域释放强啡肽A的CRF也在吗啡耐受的表达中起调节作用。
Previously, we have demonstrated that intrathecally (i.t.) administered corticotropin-releasing factor (CRF) in mice produces stimulus-specific antinociception and modulation of morphine-induced antinociception by mechanisms involving spinal kappa opioid receptors. Recently, we also have found that CRF releases immunoreactive dynorphin A, a putative endogenous kappa opioid receptor agonist, from superfused mice spinal cordsin vitro. Dynorphin A administered intracerebroventricularlly (i.c.v.) to mice has been shown to modulate the expression of morphine tolerance. In the present study, the possible modulatory effects of i.t. administered CRF as well as dynorphin A on morphine tolerance were studied in an acute tolerance model. Subcutaneous administration of 100 mg/kg of morphine sulfate (MS) to mice caused an acute tolerance to morphine-induced antinociception. The antinociceptive ED50of MS was increased from 4.4 mg/kg (naive mice) to 17.9 mg/kg (4 hours after the injection of 100 mg/kg MS). To study the modulatory effects of spinally administered CRF and dynorphin A on the expression of morphine tolerance, CRF and dynorphin A were injected i.t. at 15 min and 5 min, respectively, before testing the tolerant mice by the tail-flick assay. The antinociceptive ED50of MS in tolerant mice was decreased to 8.8 mg/kg and 7.1 mg/kg, respectively, after i.t. administration of CRF (0.1 nmol) and dynorphin A (0.2 nmol). In contrast, 0.5 nmol of alpha-helical CRF (9–41), a CRF antagonist and 0.4 nmol of norbinaltorphimine, a highly selective kappa opioid receptor antagonist, when administered i.t. at 15 min before the tail-flick test in tolerant mice, increased the antinociceptive ED50of MS to 56.6 mg/kg and 88.8 mg/kg, respectively. These data confirmed the modulatory effect of dynorphin A on morphine tolerance and suggested that CRF, which releases dynorphin A in several central nervous system regions, also plays a modulatory role in the expression of morphine tolerance.