Morphine tolerance attenuates the resolution of postoperative pain and enhances spinal microglial p38 and extracellular receptor kinase phosphorylation.
Morphine tolerance attenuates the resolution of postoperative pain and enhances spinal microglial p38 and extracellular receptor kinase phosphorylation.
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DOI：
10.1016/j.neuroscience.2010.05.030
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发表时间：
2010-08-25
期刊：
影响因子：
3.3
通讯作者：
Deleo, J. A.
中科院分区：
文献类型：
--
作者：
Horvath, R. J.;Landry, R. P.;Romero-Sandoval, E. A.;Deleo, J. A.
持续的术后疼痛是一种非常常见的现象，严重影响了在普通外科手术后出现疼痛的患者的生活。阿片类镇痛药在治疗持续性疼痛状态的疗效有限，因为其副作用包括抗痛觉耐受性。我们之前的研究表明，手术切口损伤和吗啡耐受具有相似的机制，包括脊髓胶质细胞在中枢神经系统（CNS）中的作用。因此，我们假设先前的慢性吗啡暴露会通过增加胶质离子钙结合接头蛋白1 （Iba1）和胶质纤维酸性蛋白（GFAP）蛋白表达和丝裂原活化蛋白激酶（MAPK）激活来抑制术后异位性疼痛的消退。为了验证这一假设，我们在第0天给大鼠植入皮下渗透微型泵，在第7天或第7天完成足部切口手术前后释放生理盐水或吗啡。术后每3天评估一次热痛觉过敏和机械异常性痛。到第20天，慢性吗啡减弱了术后热痛觉过敏和机械异常痛的消退。然而，脊髓背角中Iba1或GFAP的表达在两组间未见变化。对MAPK蛋白磷酸化的评估显示，与生理盐水相比，慢性吗啡治疗在第20天增强了p38和细胞外受体激酶（pERK）的磷酸化。p-p38和pERK免疫荧光仅与小胶质细胞标记物共定位，而与星形胶质细胞或神经元标记物不共定位。综上所述，这些数据表明，慢性吗啡给药与小胶质细胞p38和ERK磷酸化有关，而不依赖于Iba1和GFAP表达的变化，从而减弱了术后异常性疼痛的消退。
Persistent postoperative pain is a very common phenomenon which severely affects the lives of patients who develop it following common surgical procedures. Opioid analgesics are of limited efficacy in the treatment of persistent pain states because of side effects including antinociceptive tolerance. We have previously shown that surgical incision injury and morphine tolerance share similar mechanisms, including a central nervous system (CNS) role of spinal cord glia. We therefore hypothesized that prior chronic morphine exposure would inhibit the resolution of postoperative allodynia through increased glial ionized calcium-binding adaptor protein 1 (Iba1) and glial fibrillary acidic protein (GFAP) protein expression and mitogen activated protein kinase (MAPK) activation. To test this hypothesis, rats were implanted with subcutaneous osmotic minipumps on day zero, releasing saline or morphine for seven days preceding or seven days preceding and following paw incision surgery, which was completed on day seven. Thermal hyperalgesia and mechanical allodynia were assessed postoperatively every three days. Chronic morphine attenuated the resolution of postoperative thermal hyperalgesia and mechanical allodynia through day twenty. However, no changes in Iba1 or GFAP expression were observed in the spinal cord dorsal horn between groups. Assessment of MAPK protein phosphorylation revealed that chronic morphine administration enhanced both p38 and extracellular receptor kinase (pERK) phosphorylation compared to saline on day twenty. p-p38 and pERK immunofluorescence were only observed to colocalize with a marker of microglial cells and not with markers of astrocytes or neurons. Together, these data demonstrate that chronic morphine administration attenuates the resolution of postoperative allodynia in association with microglial p38 and ERK phosphorylation, independent of changes in Iba1 and GFAP expression.
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影响因子：
25
作者：
Ji, RR;Baba, H;Woolf, CJ
通讯作者：
Woolf, CJ
影响因子：
8.8
作者：
Ito, Naomi;Obata, Hideaki;Saito, Shigeru
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Saito, Shigeru
DOI：
10.1073/pnas.96.14.7731
发表时间：
1999-07-06
影响因子：
11.1
作者：
Mayer, DJ;Mao, JR;Price, DD
通讯作者：
Price, DD
影响因子：
2.9
作者：
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影响因子：
7.6
作者：
Raghavendra, V;Tanga, FY;DeLeo, JA
通讯作者：
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