GCH1, BH4 and pain.
GCH1, BH4 and pain.
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DOI：
10.2174/138920111798357393
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发表时间：
2011-10
影响因子：
2.8
通讯作者：
Costigan M
中科院分区：
文献类型：
--
作者：
Latremoliere A;Costigan M
理解并因此有效地治疗神经性疼痛是现代医学的挑战，因为与可以相对较好地控制的炎症不同，由于神经损伤引起的慢性疼痛对大多数当前治疗方法是难治的。在这里，我们定义了一类新的镇痛药，四氢生物蝶呤（BH 4）的合成和代谢的靶向途径。BH 4是合成5-羟色胺、多巴胺、肾上腺素、去甲肾上腺素和一氧化氮的重要辅助因子，因此，其可用性影响许多系统，包括神经元。在周围神经损伤后，感觉神经元中的BH 4水平显著增加，因此这对这些细胞的生理学产生深远影响，导致活动增加和疼痛超敏反应。这些变化主要是由于BH 4合成的限速酶GTP环化水解酶1（GCH 1）的上调。GCH 1疼痛保护性单倍型通过降低这种酶的内源性激活水平来降低各种环境中的疼痛水平，其特征在于在人类中。在这里，我们定义了BH 4稳态的控制，并讨论了该系统内的大扰动的后果，无论是通过基因突变产生的负面影响，还是在导致慢性疼痛的这种辅因子的产生病理性增加之后。我们解释了GCH 1功能降低单倍型的性质，并提出了一种“BH 4阻断”药物作为一种新型镇痛药的潜力。
Understanding and consequently treating neuropathic pain effectively is a challenge for modern medicine, as unlike inflammation, which can be controlled relatively well, chronic pain due to nerve injury is refractory to most current therapeutics. Here we define a target pathway for a new class of analgesics, tetrahydrobiopterin (BH4) synthesis and metabolism. BH4 is an essential co-factor in the synthesis of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide and as a result, its availability influences many systems, including neurons. Following peripheral nerve damage, levels of BH4 are dramatically increased in sensory neurons, consequently this has a profound effect on the physiology of these cells, causing increased activity and pain hypersensitivity. These changes are principally due to the upregulation of the rate limiting enzyme for BH4 synthesis GTP Cyclohydrolase 1 (GCH1). A GCH1 pain-protective haplotype which decreases pain levels in a variety of settings, by reducing the levels of endogenous activation of this enzyme, has been characterized in humans. Here we define the control of BH4 homeostasis and discuss the consequences of large perturbations within this system, both negatively via genetic mutations and after pathological increases in the production of this cofactor that result in chronic pain. We explain the nature of the GCH1 reduced-function haplotype and set out the potential for a ‘BH4 blocking’ drug as a novel analgesic.