FM Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Curr Pharm Biotechnol. 2011 Oct;12(10):1728-41. doi: 10.2174/138920111798357393.
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.
理解并有效治疗神经性疼痛是现代医学面临的一个挑战，因为与炎症不同，炎症可以得到相对较好的控制，而神经损伤引起的慢性疼痛对大多数当前的治疗方法都有抗性。在这里，我们定义了一类新的镇痛药——四氢生物蝶呤（BH4）合成和代谢的靶途径。BH4 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所必需的辅助因子，因此，其可用性会影响许多系统，包括神经元。外周神经损伤后，感觉神经元中的 BH4 水平显著增加，因此这对这些细胞的生理学产生了深远的影响，导致活性增加和疼痛敏感性增加。这些变化主要归因于 BH4 合成限速酶 GTP 环水解酶 1（GCH1）的上调。已经在人类中鉴定出一种 GCH1 保护性单倍型，通过降低这种酶的内源性激活水平，在多种情况下降低疼痛水平，从而减轻疼痛。在这里，我们定义了 BH4 动态平衡的控制，并讨论了该系统内的大干扰的后果，包括通过基因突变产生的负面影响，以及这种辅助因子病理性增加导致慢性疼痛的后果。我们解释了 GCH1 低功能单倍型的性质，并提出了一种“BH4 阻断”药物作为一种新型镇痛药的潜力。
