Chronic pain is a common medical complaint in the United States, reported by over 25% of adults. It is also very costly to treat, and results in additional economic burdens to society through lost work-time and productivity. Current treatments for chronic pain are often ineffective and have dangerous side-effects. Further understanding of pain transmission is needed to allow for new therapeutic strategies to treat this debilitating condition. My long term objectives are to increase our understanding of pain transmission within the nervous system and to provide a potentially novel therapeutic approach for treating pain. We have recently identified that a phosphatase called Prostatic Acid Phosphatase (PAP) is present in pain-sensing neurons. Injection of a soluble form of this protein into the spinal cord results in long-lasting analgesia, while genetic elimination of the protein results in enhanced inflammatory pain responses. The mechanisms of PAPmediated analgesia are unknown, although PAP can produce the analgesic compounds adenosine and cannabinoids in biochemical assays.
The specific aims of this proposal are to: first, test if PAP reduces cell signaling in vitro by producing analgesic molecules;second, to test if PAP suppresses pain in vivo by producing analgesic molecules;and third, test if PAP-mediated analgesia is due to decreased neuronal excitability in pain-sensing neurons. I will use a combination of molecular biology and pharmacology to study the activity of PAP in vitro and in live animals.
Understanding the mechanism of PAP-mediated analgesia will provide opportunities to develop novel approaches to treat chronic pain.
|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|
|Sowa, Nathaniel A; Street, Sarah E; Vihko, Pirkko et al. (2010) Prostatic acid phosphatase reduces thermal sensitivity and chronic pain sensitization by depleting phosphatidylinositol 4,5-bisphosphate. J Neurosci 30:10282-93|
|Sowa, Nathaniel A; Voss, Meagen K; Zylka, Mark J (2010) Recombinant ecto-5'-nucleotidase (CD73) has long lasting antinociceptive effects that are dependent on adenosine A1 receptor activation. Mol Pain 6:20|
|Sowa, Nathaniel A; Taylor-Blake, Bonnie; Zylka, Mark J (2010) Ecto-5'-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits. J Neurosci 30:2235-44|
|Sowa, Nathaniel A; Vadakkan, Kunjumon I; Zylka, Mark J (2009) Recombinant mouse PAP has pH-dependent ectonucleotidase activity and acts through A(1)-adenosine receptors to mediate antinociception. PLoS One 4:e4248|
|Zylka, Mark J; Sowa, Nathaniel A; Taylor-Blake, Bonnie et al. (2008) Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine. Neuron 60:111-22|