Analgesia by inhibiting tetrahydrobiopterin synthesis

Abstract

Physiological control of the co-factor tetrahydrobiopterin (BH4) is tight in normal circumstances but levels increase pathologically in the injured somatosensory system. BH4 is an essential co-factor in the production of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide. Excess BH4 levels cause pain, likely through excess production of one or more of these neurotransmitters or signaling molecules. The rate limiting step for BH4 production is GTP Cyclohydrolase 1 (GCH1). A human GCH1 gene haplotype exists that leads to less GCH1 transcription, translation, and therefore enzyme activity, following cellular stress. Carriers of this haplotype produce less BH4 and therefore feel less pain, especially following nerve injury where BH4 production is pathologically augmented. Sulfasalazine (SSZ) an FDA approved anti-inflammatory agent of unknown mechanism of action, has recently been shown to be a sepiapterin reductase (SPR) inhibitor. SPR is part of the BH4 synthesis cascade and is also upregulated by nerve injury. Inhibiting SPR will reduce BH4 levels and therefore should act as an analgesic. We propose SSZ as a novel anti-neuropathic pain medicine.

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

“…Furthermore, SPR inhibition in the liver was not associated with increased phenylalanine levels, indicating that sufficient BH4 levels were present in this tissue to allow phenylalanine hydroxylase function. These results are in line with the safety profile of sulfasalazine in patients, which produces very few CNS, CVS, or metabolic side effects, even when administered chronically at high doses (Costigan et al, 2012). The pharmacological blockade of SPR maintained the same relative efficacy for alleviating nerve injury-induced hypersensitivity when tested at multiple times after injury, suggesting that repeated treatment with an SPR inhibitor is possible without pharmacological tolerance.…”

“…We designed an approach to “reverse engineer” human genetic studies that have revealed an association between decreases in BH4 synthesis and reduced neuropathic (Costigan et al, 2012; Latremoliere and Costigan, 2011) and sickle cell disease pain (Belfer et al, 2014) into mechanistic analyses in mouse models. Animal models are critical to understand how, when, and where a pathway may drive a disease process and to assess therapeutic opportunities from inhibiting this pathway as well as liabilities that may occur from such inhibition.…”

“…For example, patients carrying rare Mendelian recessive loss-of-function mutations for the sodium channel Na V 1.7 are completely indifferent to pain (Dib-Hajj et al, 2013), making this channel a potential target for eliminating acute pain sensitivity (Lee et al, 2014). Although informative for nociceptive pain, rare Mendelian conditions with large phenotypes may not be effective for selecting druggable targets for chronic pathological conditions, such as neuropathic pain and chronic inflammatory disease, as the chance of associating a diminished disease phenotype with a rare polymorphism is extremely low if the phenotype only manifests in the disease state, such as after a nerve lesion (Bennett and Woods, 2014; Costigan et al, 2012). An alternative approach is to identify relatively common genetic polymorphisms with smaller effect sizes on pain outcome in disease conditions, ideally with no effect on nociceptive pain, as these may reveal potential ways to alter specific molecular mechanisms responsible for pathological pain while leaving the protective aspects of acute pain intact.…”

Intraplantar injection of tetrahydrobiopterin induces nociception in mice

“…BH4 is therefore crucial for the biosynthesis of catecholamines, serotonin and nitric oxide (NO) [1,2]. Given the pleiotropic biochemical properties of BH4, it is implicated in a number of pathological conditions, such as cardiovascular diseases, neurological diseases and psychiatric disorders [1,3] pathway has also been recognised as a potential, new target for the development of novel analgesics [2,4]. This was triggered by findings that demonstrated a link between BH4 biosynthesis and pain persistence in humans and rodents [5,6].…”

Pharmacological Management of Neuropathic Pain: Current Trends and Possible Approaches

“…Tetrahydrobiopterin (BH 4 ) levels elevated under nerve injury conditions (117). Sepiapterin reductase (SPR) is a terminal enzymatic reaction in the production of BH4.…”