PAP and NT5E inhibit nociceptive neurotransmission by rapidly hydrolyzing nucleotides to adenosine Public Deposited

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Creator
  • Taylor-Blake, Bonnie
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Street, Sarah E
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Walsh, Paul L
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Wightman, R. Mark
  • Sowa, Nathaniel A
  • Zylka, Mark J.
  • Guillot, Thomas S
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Abstract Background Prostatic acid phosphatase (PAP) and ecto-5'-nucleotidase (NT5E, CD73) produce extracellular adenosine from the nucleotide AMP in spinal nociceptive (pain-sensing) circuits; however, it is currently unknown if these are the main ectonucleotidases that generate adenosine or how rapidly they generate adenosine. Results We found that AMP hydrolysis, when measured histochemically, was nearly abolished in dorsal root ganglia (DRG) neurons and lamina II of spinal cord from Pap/Nt5e double knockout (dKO) mice. Likewise, the antinociceptive effects of AMP, when combined with nucleoside transport inhibitors (dipyridamole or 5-iodotubericidin), were reduced by 80-100% in dKO mice. In addition, we used fast scan cyclic voltammetry (FSCV) to measure adenosine production at subsecond resolution within lamina II. Adenosine was maximally produced within seconds from AMP in wild-type (WT) mice but production was reduced >50% in dKO mice, indicating PAP and NT5E rapidly generate adenosine in lamina II. Unexpectedly, we also detected spontaneous low frequency adenosine transients in lamina II with FSCV. Adenosine transients were of short duration (<2 s) and were reduced (>60%) in frequency in Pap -/- , Nt5e -/- and dKO mice, suggesting these ectonucleotidases rapidly hydrolyze endogenously released nucleotides to adenosine. Field potential recordings in lamina II and behavioral studies indicate that adenosine made by these enzymes acts through the adenosine A1 receptor to inhibit excitatory neurotransmission and nociception. Conclusions Collectively, our experiments indicate that PAP and NT5E are the main ectonucleotidases that generate adenosine in nociceptive circuits and indicate these enzymes transform pulsatile or sustained nucleotide release into an inhibitory adenosinergic signal.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Sarah E Street et al.; licensee BioMed Central Ltd.
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Journal title
  • Molecular Pain
Journal volume
  • 7
Journal issue
  • 1
Page start
  • 80
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1744-8069
Bibliographic citation
  • Molecular Pain. 2011 Oct 19;7(1):80
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  • Open Access
Publisher
  • BioMed Central Ltd
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