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).

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