Inhibition of GTP cyclohydrolase reduces cancer pain in mice and enhances analgesic effects of morphine
Inhibition of GTP cyclohydrolase reduces cancer pain in mice and enhances analgesic effects of morphine
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抑制 GTP 环水解酶可减轻小鼠癌症疼痛并增强吗啡的镇痛作用
DOI：
10.1007/s00109-012-0927-7
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Tegeder I.
中科院分区：
文献类型：
--
作者：
Pickert G;Myrczek T;Rückert S;Weigert A;Häussler A;Ferreirós N;Brüne B;Lötsch J;Tegeder I.
GTP环水解酶基因（GCH1）的非编码多态性降低了人类慢性疼痛的风险，提示GCH1抑制剂可作为镇痛药。我们评估了GCH1抑制剂二氨基羟基嘧啶（DAHP）对小鼠黑色素瘤和肉瘤癌痛模型的伤害感受和炎症的影响，以及它与吗啡在镇痛效果和呼吸抑制方面的联合作用。GCH1抑制并未降低荷瘤足鼠肿瘤诱发的伤害性超敏反应。然而，通过分析对侧爪子，DAHP减少了黑色素瘤和肉瘤引起的全身痛觉过敏。GCH1抑制增加了炎性水肿和肿瘤周围多形核白细胞的浸润，但减少了脊髓中肿瘤诱发的小胶质细胞的激活，这表明对肿瘤的局部免疫攻击的增加可能避免了全身疼痛过敏。当与高剂量或低剂量吗啡合用时，GCH1抑制增加并延长了阿片类药物的镇痛作用。然而，它并没有增加吗啡引起的呼吸抑制。相反，gch1产物四氢生物蝶呤引起痛觉过敏，拮抗吗啡的抗伤性作用，并加重吗啡引起的呼吸抑制，后者由cGMP类似物模拟，表明呼吸作用部分通过BH4-NO-cGMP途径介导。观察到GCH1在肿瘤模型中的抑制作用及其在不增加吗啡毒性的情况下增强吗啡诱发的抗痛觉作用，提示GCH1抑制剂可能可作为阿片类药物在癌症患者中的联合治疗药物。
Noncoding polymorphisms of the GTP cyclohydrolase gene (GCH1) reduce the risk for chronic pain in humans suggesting GCH1 inhibitors as analgesics. We assessed the effects of the GCH1 inhibitor diaminohydroxypyrimidine (DAHP) on nociception and inflammation in a mouse melanoma and a sarcoma cancer pain model, and its co-effects with morphine in terms of analgesic efficacy and respiratory depression. GCH1 inhibition did not reduce the tumor-evoked nociceptive hypersensitivity of the tumor-bearing paw. However, DAHP reduced melanoma- and sarcoma-evoked systemic hyperalgesia as determined by analyzing contralateral paws. GCH1 inhibition increased the inflammatory edema and infiltration with polymorphonuclear leukocytes surrounding the tumor but reduced the tumor-evoked microglia activation in the spinal cord suggesting that an increase of the local immune attack against the tumor may avoid general pain hypersensitivity. When used in combination with morphine at high or low doses, GCH1 inhibition increased and prolonged the analgesic effects of the opioid. It did not, however, increase the respiratory depression caused by morphine. Conversely, the GCH1-product, tetrahydrobiopterin, caused hyperalgesia, antagonized antinociceptive effects of morphine, and aggravated morphine-evoked respiratory depression, the latter mimicked by a cGMP analog suggesting that respiratory effects were partly mediated through the BH4–NO–cGMP pathway. The observed effects of GCH1 inhibition in the tumor model and its enhancement of morphine-evoked antinociception without increase of morphine toxicity suggest that GCH1 inhibitors might be useful as co-therapeutics for opioids in cancer patients.
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DOI：
10.1152/japplphysiol.90548.2008
发表时间：
2009
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
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作者：
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影响因子：
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影响因子：
9.7
作者：
K. Schroecksnadel;B. Frick;C. Winkler;L. Fuith;D. Fuchs
通讯作者：
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DOI：
10.1073/pnas.1002404107
发表时间：
2010-08-03
影响因子：
11.1
作者：
Watschinger, Katrin;Keller, Markus A.;Werner, Ernst R.
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阻断四氢生物蝶呤合成可保护大鼠短暂前脑缺血后的神经元：辅因子的新作用
影响因子：
5.3
作者：
Sunghee Cho;B. Volpe;Y. Bae;O. Hwang;H. Choi;J. Gal;L. Park;C. K. Chu;Jinfa Du;T. Joh
通讯作者：
T. Joh