Damage to peripheral nerves often leads to patient suffering from chronic neuropathic pain. Possible causes of neuropathic pain include the disruption of cellular processes that are dependent on intracellular calcium homeostasis. In dorsal root ganglion neurons (DRGs), calcium regulates neurotransmitter release into the spinal cord, cellular excitability, neuronal growth and repair, gene transcription and cell death. Tetrahydrobiopterin (BH4), a small enzymatic cofactor, was shown to modulate calcium currents in DRGs and its upregulation is related to allodynia and hypersensitivity to painful stimuli. Genetic mutations that prevent the upregulation of BH4 synthesis after nerve injury produces a pain-protective haplotype in humans. The purpose of this project is to understand how BH4 is involved in the persistence of pain after nerve injury. 1)To identify which specific calcium ion channels BH4 regulates in naive dorsal root ganglion neurons calcium imaging and electrophysiology techniques will be used. Results from these tests will provide information on the types of ion channels that are directly or indirectly affected by BH4 activity. 2)A rodent model of neuropathic pain will be used to determine the effects of exogenous application of BH4 on injured DRGs. Calcium currents and membrane potential will be examined at various timepoints after injury to establish a time course of altered ion channel function. 3)lnhibitors of BH4 cofactor activity will be used to determine which enzymatic pathway dominates or is altered after injury. 4)Behavioral studies will be needed to evaluate how genetic downregulation of BH4 synthesis in the DRG, affects cold and mechanical sensitivity after spared nerve injury in transgenic mice. There are currently no pharmaceutical interventions that effectively eliminate all symptoms of chronic neuropathic pain without being accompanied by various unwanted side effects. Identifying the actions of BH4 in the cell bodies of sensory neurons could lead to potential molecular targets for analgesics to relieve symptoms of chronic pain while eliminating side effects.
|Ibarra, Yessenia; Blair, Nathaniel T (2013) Benzoquinone reveals a cysteine-dependent desensitization mechanism of TRPA1. Mol Pharmacol 83:1120-32|