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Neuropsychopharmacology. 2011 January; 36(1): 358.
Published online 2010 November 30. doi:  10.1038/npp.2010.141
PMCID: PMC3055498

Emerging Roles for Ectonucleotidases in Pain-Sensing Neurons

Nociceptive neurons located in the dorsal root ganglia detect painful stimuli and can be sensitized following inflammation or nerve injury. Many analgesics have ‘antinociceptive' effects, which mean these drugs can reduce noxious thermal and mechanical sensitization—two symptoms that are associated with chronic pain. One drug that has been studied for its antinociceptive effects in rodents and humans is adenosine (Sawynok and Liu, 2003). Adenosine exerts its antinociceptive effects by activating the adenosine A1 receptor (A1R). A1R is expressed by nociceptive neurons and many other cells of the body, suggesting localized activation of this receptor in nociceptive neurons might inhibit pain without producing cardiovascular and other effects that are associated with systemic A1R activation. Recently, several new studies found that A1R can be activated locally near nociceptive neurons or their axons by ectonucleotidases—a class of enzymes that hydrolyze extracellular adenine nucleotides to adenosine. Moreover, this localized A1R activation was sufficient to inhibit chronic pain in animal models.

In the first set of studies, our lab found that prostatic acid phosphatase (PAP) and ecto-5′-nucleotidase (NT5E, also known as CD73) function as ectonucleotidases in nociceptive neurons (Sowa et al, 2010a; Zylka et al, 2008). PAP and NT5E can each hydrolyze extracellular adenosine 5′-monophosphate (AMP) to adenosine. In histochemical assays, AMP hydrolysis was reduced (but not eliminated) in nociceptive neurons from PAP and NT5E knockout mice. PAP and NT5E knockout mice also showed enhanced nociception in models of inflammatory and neuropathic pain. These enhanced responses from genetically eliminating enzymes that make adenosine were similar to the enhanced nociception phenotypes observed by Wu and colleagues in mice lacking A1R (Wu et al, 2005).

PAP and NT5E can each be purified as nonmembrane-bound enzymatically active proteins. This feature provided us with a means to transiently increase the amount of PAP or NT5E activity in vivo. Specifically, we found that intrathecal injection of soluble PAP or NT5E protein had dose-dependent and long-lasting antinociceptive effects in animal models of inflammatory pain and neuropathic pain (Sowa et al, 2010b; Zylka et al, 2008). The antinociceptive effects of PAP lasted for 3 days after a single intrathecal injection whereas the antinociceptive effects of NT5E lasted 2 days. The antinociceptive effects of both enzymes were dependent on A1R activation, suggesting that PAP and NT5E act through their ability to generate adenosine from AMP. Moreover, these findings suggest ectonucleotidases could be developed as enzyme-based treatments for some forms of chronic pain.

In another recent study, Goldman et al. (2010) found that localized A1R activation underlies the antinociceptive effects of acupuncture. Manual stimulation of acupuncture needles resulted in localized extracellular increases in nucleotides (ATP, ADP, and AMP) and adenosine. The ectonucleotidases responsible for generating adenosine were not identified in this study; however, indirect evidence suggests PAP may be a candidate. Collectively, these studies reveal roles for localized A1R activation and ectonucleotidases in nociceptive neurons and offer new approaches for treating chronic pain.

Notes

The authors declare no conflict of interest.

References

  • Goldman N, Chen M, Fujita T, Xu Q, Peng W, Liu W, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci. 2010;13:883–888. [PubMed]
  • Sawynok J, Liu XJ. Adenosine in the spinal cord and periphery: release and regulation of pain. Prog Neurobiol. 2003;69:313–340. [PubMed]
  • Sowa NA, Taylor-Blake B, Zylka MJ. Ecto-5′-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits. J Neurosci. 2010a;30:2235–2244. [PMC free article] [PubMed]
  • Sowa NA, Voss MK, Zylka MJ. Recombinant ecto-5′-nucleotidase (CD73) has long lasting antinociceptive effects that are dependent on adenosine A1 receptor activation. Mol Pain. 2010b;6:20. [PMC free article] [PubMed]
  • Wu WA, Hao JX, Halldner L, Lovdahl C, DeLander GE, Wiesenfeld-Hallin Z, et al. Increased nociceptive responses in mice lacking the A1 receptor. Pain. 2005;113:395–404. [PubMed]
  • Zylka MJ, Sowa NA, Taylor-Blake B, Twomey MA, Herrala A, Voikar V, et al. Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine. Neuron. 2008;60:111–122. [PMC free article] [PubMed]

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