Review
Pain-relieving prospects for adenosine receptors and ectonucleotidases

https://doi.org/10.1016/j.molmed.2010.12.006Get rights and content

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 A1 receptor-dependent antinociceptive effects in inflammatory and neuropathic pain models. Furthermore, recent findings indicate that spinal adenosine A2A 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.

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).

References (94)

  • T. Nakagawa

    Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance

    Neuroscience

    (2007)
  • M. Tsuda

    Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia

    Trends Neurosci.

    (2005)
  • R.W. Gereau et al.

    Potentiation of cAMP responses by metabotropic glutamate receptors depresses excitatory synaptic transmission by a kinase-independent mechanism

    Neuron

    (1994)
  • J.M. Brundege

    The role of cyclic AMP as a precursor of extracellular adenosine in the rat hippocampus

    Neuropharmacology

    (1997)
  • J. Sawynok et al.

    Adenosine in the spinal cord and periphery: release and regulation of pain

    Prog. Neurobiol.

    (2003)
  • M.J. Zylka

    Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine

    Neuron

    (2008)
  • I.L. Torres

    Effect of chronic and acute stress on ectonucleotidase activities in spinal cord

    Physiol. Behav.

    (2002)
  • W.P. Wu

    Increased nociceptive response in mice lacking the adenosine A1 receptor

    Pain

    (2005)
  • G.J. Keil et al.

    Altered sensory behaviors in mice following manipulation of endogenous spinal adenosine neurotransmission

    Eur. J. Pharmacol.

    (1996)
  • L. Tian

    Excitatory synaptic transmission in the spinal substantia gelatinosa is under an inhibitory tone of endogenous adenosine

    Neurosci. Lett.

    (2010)
  • J.R. Rozisky

    Neonatal morphine exposure alters E-NTPDase activity and gene expression pattern in spinal cord and cerebral cortex of rats

    Eur. J. Pharmacol.

    (2010)
  • P. Vihko

    Secretion into and elimination from blood circulation of prostate specific acid phosphatase, measured by radioimmunoassay

    J. Urol.

    (1982)
  • C. Post

    Antinociceptive effects in mice after intrathecal injection of 5′-N-ethylcarboxamide adenosine

    Neurosci. Lett.

    (1984)
  • I.S. Daniels

    A role of erythrocytes in adenosine monophosphate initiation of hypometabolism in mammals

    J. Biol. Chem.

    (2010)
  • Z.Q. Zhao

    Neural mechanism underlying acupuncture analgesia

    Prog. Neurobiol.

    (2008)
  • E. Ernst

    Acupuncture: what does the most reliable evidence tell us?

    J. Pain Symptom Manage.

    (2009)
  • A. Poon et al.

    Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat

    Pain

    (1998)
  • M.P. Schaddelee

    Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and anti-nociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain

    Eur. J. Pharmacol.

    (2005)
  • R. Iijima

    The extracellular adenosine deaminase growth factor, ADGF/CECR1, plays a role in Xenopus embryogenesis via the adenosine/P1 receptor

    J. Biol. Chem.

    (2008)
  • K. Golembiowska

    Modulation of adenosine release from rat spinal cord by adenosine deaminase and adenosine kinase inhibitors

    Brain Res.

    (1995)
  • K.A. Jacobson et al.

    Adenosine receptors as therapeutic targets

    Nat. Rev. Drug Discov.

    (2006)
  • S.M. Reppert

    Molecular cloning and characterization of a rat A1-adenosine receptor that is widely expressed in brain and spinal cord

    Mol. Endocrinol.

    (1991)
  • J. Sawynok

    Adenosine and ATP receptors

    Handb. Exp. Pharmacol.

    (2007)
  • M. Hayashida

    Clinical application of adenosine and ATP for pain control

    J. Anesth.

    (2005)
  • R. Karlsten et al.

    An A1-selective adenosine agonist abolishes allodynia elicited by vibration and touch after intrathecal injection

    Anesth. Analg.

    (1995)
  • G. Lind

    Drug-enhanced spinal stimulation for pain: a new strategy

    Acta Neurochir. Suppl.

    (2007)
  • T. King

    Unmasking the tonic-aversive state in neuropathic pain

    Nat. Neurosci.

    (2009)
  • A.C. Dolphin

    Calcium-dependent currents in cultured rat dorsal root ganglion neurones are inhibited by an adenosine analogue

    J. Physiol.

    (1986)
  • M. Mynlieff et al.

    Adenosine acting at an A1 receptor decreases N-type calcium current in mouse motoneurons

    J. Neurosci.

    (1994)
  • T.J. Martin

    Opioid self-administration in the nerve-injured rat: relevance of antiallodynic effects to drug consumption and effects of intrathecal analgesics

    Anesthesiology

    (2007)
  • P.K. Zahn

    Adenosine A1 but not A2a receptor agonist reduces hyperalgesia caused by a surgical incision in rats: a pertussis toxin-sensitive G protein-dependent process

    Anesthesiology

    (2007)
  • D.J. Langford

    Coding of facial expressions of pain in the laboratory mouse

    Nat. Methods

    (2010)
  • T.J. Gan et al.

    Adenosine as a non-opioid analgesic in the perioperative setting

    Anesth. Analg.

    (2007)
  • A.S. Habib

    Phase 2, double-blind, placebo-controlled, dose-response trial of intravenous adenosine for perioperative analgesia

    Anesthesiology

    (2008)
  • N.A. Sowa

    Prostatic acid phosphatase reduces thermal sensitivity and chronic pain sensitization by depleting phosphatidylinositol 4,5-bisphosphate

    J. Neurosci.

    (2010)
  • Y. Matsuka

    Altered ATP release and metabolism in dorsal root ganglia of neuropathic rats

    Mol. Pain

    (2008)
  • C.J. Dixon

    Regulation of epidermal homeostasis through P2Y2 receptors

    Br. J. Pharmacol.

    (1999)
  • Cited by (0)

    View full text