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|Title:||Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: A novel therapy for neuropathic pain|
|Citation:||Journal of Neuroscience, 2009; 29(44):14015-14025|
|Lisa C. Loram, Jacqueline A. Harrison, Evan M. Sloane, Mark R. Hutchinson, Paige Sholar, Frederick R. Taylor, Debra Berkelhammer, Benjamen D. Coats, Stephen Poole, Erin D. Milligan, Steven F. Maier, Jayson Rieger, and Linda R. Watkins|
|Abstract:||Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A(2A)Rs) 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 A(2A)R agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single intrathecal injection of the A(2A)R 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 A(2A)R 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 A(2A)R 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 A(2A)Rs 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.|
|Keywords:||Animals; Rats; Rats, Sprague-Dawley; Pain; Neuralgia; Piperidines; Receptor, Adenosine A2A; Pain Measurement; Injections, Spinal; Male; Adenosine A2 Receptor Agonists|
|Description:||Copyright © 2009 Society for Neuroscience|
|Appears in Collections:||Medicine publications|
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