Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2.
Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2.
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DOI：
10.1016/j.pain.2010.02.042
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发表时间：
2010-09
期刊：
影响因子：
7.4
通讯作者：
De Leo JA
中科院分区：
文献类型：
--
作者：
Horvath RJ;Romero-Sandoval AE;De Leo JA
阿片类药物的镇痛耐受性是一种广为人知的现象，它严重限制了阿片类药物治疗慢性疼痛综合征的临床疗效。然而，驱动抗伤害性耐受的机制还不太清楚。我们以前已经表明，神经胶质细胞在吗啡耐受性的发展中起着重要作用，并且神经胶质细胞调节剂的施用减弱了耐受性的形成。最近，我们已经证明，在体外培养的小胶质细胞中，吗啡通过直接μ阿片受体信号增强小胶质细胞Iba1表达和P2X4受体介导的小胶质细胞迁移。我们假设P2X4受体驱动吗啡耐受和调节吗啡诱导的脊髓胶质细胞反应。此外，我们假设血管周围小胶质细胞在吗啡耐受中发挥作用，P2X4受体表达调节血管周围小胶质细胞ED 2的表达。为了验证这些假设，大鼠皮下植入渗透微型泵释放吗啡或生理盐水7天。从吗啡治疗前三天开始，每天鞘内注射P2X4受体反义寡核苷酸（asODN），以选择性地抑制P2X4受体表达。P2X4受体asODN处理抑制吗啡诱导的P2X4受体表达，并阻断对全身施用吗啡的抗伤害性耐受。P2X4受体asODN处理后，脊髓离子钙结合蛋白（Iba 1）、胶质细胞酸性蛋白（GFAP）和μ阿片受体蛋白表达也明显减少。慢性吗啡也降低血管周围小胶质细胞ED 2的表达，这是逆转P2X4受体asODN。总之，这些数据表明，调节P2X4受体表达的小胶质细胞和血管周围的小胶质细胞可以证明是一个有吸引力的目标，辅助治疗，以减弱阿片类药物诱导的抗伤害耐受。
Antinociceptive tolerance to opioids is a well-described phenomenon, which severely limits the clinical efficacy of opioids for the treatment of chronic pain syndromes. The mechanisms that drive antinociceptive tolerance, however, are less well understood. We have previously shown that glia have a central role in the development of morphine tolerance and that administration of a glial modulating agent attenuated tolerance formation. Recently, we have demonstrated that morphine enhances microglial Iba1 expression and P2X4 receptor-mediated microglial migration via direct μ opioid receptor signaling in in vitro microglial cultures. We hypothesize that P2X4 receptors drive morphine tolerance and modulate morphine-induced spinal glial reactivity. Additionally, we hypothesize that perivascular microglia play a role in morphine tolerance and that P2X4 receptor expression regulates perivascular microglia ED2 expression. To test these hypotheses, rats were implanted with osmotic minipumps releasing morphine or saline subcutaneously for seven days. Beginning three days prior to morphine treatment, P2X4 receptor antisense oligonucleotide (asODN) was injected intrathecally daily, to selectively inhibit P2X4 receptor expression. P2X4 receptor asODN treatment inhibited morphine-induced P2X4 receptor expression and blocked antinociceptive tolerance to systemically administered morphine. P2X4 receptor asODN treatment also attenuated the morphine-dependent increase of spinal ionized calcium binding protein (Iba1), glial fibrillary acidic protein (GFAP) and μ opioid receptor protein expression. Chronic morphine also decreased perivascular microglial ED2 expression, which was reversed by P2X4 receptor asODN. Together, these data suggest that modulation of P2X4 receptor expression on microglia and perivascular microglia may prove an attractive target for adjuvant therapy to attenuate opioid-induced antinociceptive tolerance.
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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：
3.4
作者：
Calvo, CF;Cesselin, F;Glowinski, J
通讯作者：
Glowinski, J
影响因子：
7.4
作者：
Ledeboer, A;Sloane, EM;Watkins, LR
通讯作者：
Watkins, LR
影响因子：
3.4
作者：
Ammon-Treiber, S;Höllt, V
通讯作者：
Höllt, V
影响因子：
4.2
作者：
Irino, Yasuhiro;Nakamura, Yasuko;Ohsawa, Keiko
通讯作者：
Ohsawa, Keiko