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The Journal of Neuroscience, November 4, 2009, 29(44):14015-14025; doi:10.1523/JNEUROSCI.3447-09.2009
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Behavioral/Systems/Cognitive
Enduring Reversal of Neuropathic Pain by a Single Intrathecal Injection of Adenosine 2A Receptor Agonists: A Novel Therapy for Neuropathic Pain
Lisa C. Loram,1 Jacqueline A. Harrison,1 Evan M. Sloane,1 Mark R. Hutchinson,1,2 Paige Sholar,1 Frederick R. Taylor,1 Debra Berkelhammer,1 Benjamen D. Coats,1 Stephen Poole,3 Erin D. Milligan,1,4 Steven F. Maier,1 Jayson Rieger,5 andLinda R. Watkins1 1Department of Psychology and Center for Neurosciences, University of Colorado at Boulder, Boulder, Colorado 80309-0345, 2Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia, 3National Institute of Biological Standards and Control, Potters Bar, South Mimms, Hertfordshire EN6 3QG, United Kingdom, 4Department of Neurosciences, University of New Mexico, Albuquerque, New Mexico 87131, and 5PGxHealth, A Division of Clinical Data, Inc., Charlottesville, Virginia 22902
Correspondence should be addressed to Dr. Lisa C. Loram, Department of Psychology and Center for Neurosciences, UCB 345, University of Colorado at Boulder, Boulder, CO 80309-0345. Email: lisa.loram{at}colorado.edu
Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A2ARs) decrease proinflammatory cytokine release and increase release of the potent anti-inflammatory cytokine, interleukin-10 (IL-10). Given the growing literature supporting that glial proinflammatory cytokines importantly contribute to neuropathic pain and that IL-10 can suppress such pain, we evaluated the effects of intrathecally administered A2AR agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single intrathecal injection of the A2AR agonists 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313) or 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680), 10–14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 weeks. Neither drug altered the nociceptive responses of sham-operated controls. An A2AR antagonist [ZM241385 (4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol)] coadministered intrathecally with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia but had no effect on allodynia in the absence of the A2AR agonist. ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4–L6 spinal cord segments both 1 and 4 weeks after a single intrathecal ATL313 administration. Neutralizing IL-10 antibodies administered intrathecally transiently abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region. Activation of A2ARs after intrathecal administration may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.
Received July 14, 2009; revised Sept. 4, 2009; accepted Oct. 9, 2009.
Correspondence should be addressed to Dr. Lisa C. Loram, Department of Psychology and Center for Neurosciences, UCB 345, University of Colorado at Boulder, Boulder, CO 80309-0345. Email: lisa.loram{at}colorado.edu
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