More Americans suffer from chronic pain than heart disease, diabetes and cancer combined. Unfortunately, existing analgesics are not completely effective for all pain conditions and have serious side effects. These facts highlight what is undoubtedly a critical challenge for modern biomedical research-the need to provide pain relief without serious side effects. We will directly address this challenge by harnessing ectonucleotidases that are found endogenously in nociceptive (pain-sensing) circuits in dorsal root ganglia (DRG) and spinal cord. Ectonucleotidases degrade purine nucleotides (like ATP and ADP) that cause pain into adenosine-a compound that has analgesic properties in rodents and humans. Adenosine suppresses pain by acting through A1-adenosine receptors. To fully harness ectonucleotidases for the treatment of pain, we will identify all of the ectonucleotidases that metabolize nucleotides to adenosine in nociceptive circuits and then determine if these enzymes can be used alone or in combination to treat acute and chronic pain. We will utilize genetically modified mice that are missing these enzymes, recombinant ectonucleotidase proteins, behavioral assays and patch clamp electrophysiology for these experiments. In addition, we will use medicinal chemistry to synthesize adenosine prodrugs that can be converted into potent A1-adenosine receptor agonists by ectonucleotidases. We will measure the stability of these prodrugs in serum and use behavioral and physiological assays to assess analgesic efficacy and side effects. We will also test ectonucleotidases and prodrugs for efficacy in animal models of chronic inflammatory and neuropathic pain.
These studies will allow us to develop new proteins and small molecules that target ectonucleotidases for the treatment of acute and chronic pain. In addition, these studies have the potential to transform how we treat pain in millions of patients with fewer side effects.
|Wright, Brittany D; Loo, Lipin; Street, Sarah E et al. (2014) The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron 82:836-47|
|McCoy, Eric S; Zylka, Mark J (2014) Enhanced behavioral responses to cold stimuli following CGRP? sensory neuron ablation are dependent on TRPM8. Mol Pain 10:69|
|Rittiner, Joseph E; Brings, Victoria E; Zylka, Mark J (2014) Overexpression of diacylglycerol kinase ? enhances G?q-coupled G protein-coupled receptor signaling. Mol Pharmacol 85:800-10|
|McCoy, Eric S; Taylor-Blake, Bonnie; Street, Sarah E et al. (2013) Peptidergic CGRPýý primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold. Neuron 78:138-51|
|Hurt, Julie K; Fitzpatrick, Brendan J; Norris-Drouin, Jacqueline et al. (2012) Secretion and N-linked glycosylation are required for prostatic acid phosphatase catalytic and antinociceptive activity. PLoS One 7:e32741|
|Huang, Hsien-Sung; Allen, John A; Mabb, Angela M et al. (2012) Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481:185-9|
|Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A et al. (2012) AMP is an adenosine A1 receptor agonist. J Biol Chem 287:5301-9|
|Hurt, Julie K; Zylka, Mark J (2012) PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain. Mol Pain 8:28|
|Street, Sarah E; Walsh, Paul L; Sowa, Nathaniel A et al. (2011) PAP and NT5E inhibit nociceptive neurotransmission by rapidly hydrolyzing nucleotides to adenosine. Mol Pain 7:80|
|Zylka, Mark J (2011) Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Mol Med 17:188-96|
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