pharmazentrum frankfurt, ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, Hs 74, 60590 Frankfurt, Germany.
J Mol Med (Berl). 2012 Dec;90(12):1473-86. doi: 10.1007/s00109-012-0927-7. Epub 2012 Jun 17.
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.
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 抑制剂二氨基羟嘧啶（DAHP）在小鼠黑色素瘤和肉瘤癌痛模型中对伤害感受和炎症的影响，以及其在镇痛效果和呼吸抑制方面与吗啡的协同作用。GCH1 抑制并没有减轻荷瘤鼠的肿瘤诱发的痛觉过敏。然而，DAHP 降低了黑色素瘤和肉瘤诱发的对侧爪的全身性痛觉过敏。GCH1 抑制增加了肿瘤周围的炎症性水肿和多形核白细胞浸润，但减少了脊髓中肿瘤诱发的小胶质细胞激活，这表明增加局部免疫攻击肿瘤可能避免全身痛觉过敏。当与高剂量或低剂量吗啡联合使用时，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 的产物四氢生物蝶呤引起痛觉过敏，拮抗吗啡的抗伤害感受作用，并加重吗啡引起的呼吸抑制，后者被 cGMP 类似物模拟，表明呼吸效应部分通过 BH4-NO-cGMP 途径介导。在肿瘤模型中观察到的 GCH1 抑制作用及其增强吗啡诱发的镇痛作用而不增加吗啡毒性，表明 GCH1 抑制剂可能作为癌症患者阿片类药物的辅助治疗药物有用。
