Trends in Molecular Medicine
ReviewPain-relieving prospects for adenosine receptors and ectonucleotidases
Section snippets
Adenosine as a therapeutic agent for pain
Adenosine is a purine nucleoside that can signal through four distinct receptors (A1R, A2AR, A2BR and A3R; also known as ADORA1, ADORA2A, ADORA2B and ADORA3). Of these receptors, A1R has received the greatest attention in pain-related studies. A1R is a Gi/o-coupled receptor that is expressed in nociceptive (pain-sensing) neurons, spinal cord neurons and other cells of the body 1, 2, 3, 4. Agonists of this receptor have well-studied antinociceptive effects in rodents when injected intrathecally,
ATP as a source of extracellular adenosine
Many of the studies reviewed here focus on the antinociceptive effects of extracellular adenosine, so it is worth reviewing where this nucleoside comes from and how it is metabolized. All cells release ATP at low levels, and release is enhanced on stimulation, inflammation, pH change, hypoxia, tissue damage or nerve injury 26, 27, 28, 29, 30, 31, 32. Release can occur via vesicular and nonvesicular mechanisms (Figure 1a) that vary in importance, depending on cell type 33, 34, 35, 36. For
Antinociceptive effects of acupuncture require A1R activation
Acupuncture has been used for millennia to treat pain in humans. Perhaps surprisingly, acupuncture also has antinociceptive effects in rodents. Although there is ongoing debate as to whether the placebo effect contributes to acupuncture pain relief in humans 71, 72, this argument is unlikely to apply to rodents. In mice, acupuncture needle stimulation caused the localized release of nucleotides (ATP, ADP and AMP) and of adenosine [73]. These antinociceptive effects of acupuncture were entirely
A1R activation inhibits nociceptive sensitization by depleting PIP2
It was recently found that sustained A1R activation by PAP leads to phospholipase C-mediated depletion of PIP2 in cultured cells and in mouse DRG [24]. Depletion of this essential phosphoinositide reduced noxious thermosensation, in part through inhibition of transient receptor potential cation channel V1 (TRPV1), a thermosensory channel that requires PIP2 for activity [77]. Depletion of PIP2 also enduringly reduced thermal hyperalgesia and mechanical allodynia caused by inflammation, nerve
Concluding remarks
Previous efforts aimed at treating pain with adenosine have failed, and cardiovascular side effects (Box 1) negate the use of full A1R agonists in pill form (systemic delivery). However, in no way do these failures negate the use of other routes of administration, more creative drug design, use of ectonucleotidases or use of partial agonists, such as those that seem to be safe when administered systemically in humans (Box 1). There is no question that adenosine receptors have been validated in
Acknowledgments
I thank Julie Hurt and Sarah Street for comments. This work was supported by grants from NINDS (R01NS060725, R01NS067688).
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