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The development of novel analgesics for chronic pain in the last 2 decades has proven virtually intractable, typically failing due to lack of efficacy and dose-limiting side effects. Identified through unbiased gene expression profiling experiments in rats and confirmed by human genome-wide association studies, the role of excessive tetrahydrobiopterin (BH4) in chronic pain has been validated by numerous clinical and preclinical studies. BH4 is an essential cofactor for aromatic amino acid hydroxylases, nitric oxide synthases, and alkylglycerol monooxygenase so a lack of BH4 leads to a range of symptoms in the periphery and central nervous system (CNS). An ideal therapeutic goal therefore would be to block excessive BH4 production, while preventing potential BH4 rundown. In this review, we make the case that sepiapterin reductase (SPR) inhibition restricted to the periphery (i.e., excluded from the spinal cord and brain), is an efficacious and safe target to alleviate chronic pain. First, we describe how different cell types that engage in BH4 overproduction and contribute to pain hypersensitivity, are themselves restricted to peripheral tissues and show their blockade is sufficient to alleviate pain. We discuss the likely safety profile of peripherally restricted SPR inhibition based on human genetic data, the biochemical alternate routes of BH4 production in various tissues and species, and the potential pitfalls to predictive translation when using rodents. Finally, we propose and discuss possible formulation and molecular strategies to achieve peripherally restricted, potent SPR inhibition to treat not only chronic pain but other conditions where excessive BH4 has been demonstrated to be pathological.

Subduction zone volcanoes may show irregular bursts of high-frequency or high-magnitude activity. The andesitic Mt. Tongariro (New Zealand) experienced an unusual 85 and calcic plagioclase (An73–89), while evolved magma end members contained Mg# < 75 clinopyroxene and An56–63 plagioclase. Rim-zoning of these phases reflect timespans for equilibration of evolved and mafic crystals to a hybrid melt. The whole-rock compositions of lapilli reflect the hybrid basaltic andesite to andesite, but show diverse glass compositions (56–72 wt% SiO2) implying that magma homogenisation was incomplete before eruption. Crystal-melt equilibria of olivine and clinopyroxene rims reveal polybaric crystallisation, showing mean depths of ~8.5 km (230 ± 70 MPa) at temperatures between 1000 and 1150 °C. At the northern margins of the system, volatile-rich amphibole-bearing magmas were erupted for the first and last eruption of the series, creating stable Plinian eruption styles. This flare-up was previously interpreted as tectonically controlled, however, there were low tectonic extension rates at that time. Hence, we propose instead that magma pressure build-up and recharge beneath Mt. Tongariro drove the inflation and homogenisation of the magma system, fueling the ~200 year-long flare-up. Subsequently, the magma supply system returned to pre-Mangamate activity levels, so that vigorous recharge would be required for a return to >M 4 eruptions.

Data set to accompany journal article, No funding grants were involved in this project