Pain-relieving prospects for adenosine receptors and ectonucleotidases

Abstract

Adenosine receptor agonists have potent antinociceptive effects in diverse preclinical models of chronic pain. By contrast, the efficacy of adenosine and adenosine receptor agonists in treating pain in humans is unclear. Two ectonucleotidases that generate adenosine in nociceptive neurons were recently identified. When injected spinally, these enzymes have long-lasting adenosine A(1) receptor-dependent antinociceptive effects in inflammatory and neuropathic pain models. Furthermore, recent findings indicate that spinal adenosine A(2A) receptor activation can enduringly inhibit neuropathic pain symptoms. Collectively, these studies suggest the possibility of treating chronic pain in humans by targeting specific adenosine receptor subtypes in anatomically defined regions with agonists or with ectonucleotidases that generate adenosine.

Figure 1

Proteins that regulate extracellular adenosine levels also influence adenosine receptor activation. (a). ATP can be released from neurons and/or glial cells by vesicular and non-vesicular mechanisms. Vesicular nucleotide transporter (VNUT/ SLC17A9), volume activated anion channels (VAAC), Connexin 43 (Cx43). Ectonucleotidases (pacman-like symbol) hydrolyze extracellular nucleotides to adenosine. Adenosine acts on adenosine receptors, including A₁R. Sustained A₁R activation reduces PIP₂ levels and has antinociceptive effects in animals. Adenosine is removed from the extracellular space by metabolic enzymes or by transport into cells via equilibrative nucleoside transporters (ENTs). AMP deaminase metabolizes AMP to inosine monophosphate (IMP). Blue = proteins linked to nociceptive mechanisms by genetic experiments. (b). Structures of 5’-AMP and adenosine.