title: Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: a novel therapy for neuropathic pain.
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.
authors.affiliation: Department of Psychology and Center for Neurosciences, University of Colorado at Boulder, Boulder, CO 80309-0345, USA. lisa.loram@colorado.edu
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Harrison
authors.forename: Evan M
authors.initials: EM
authors.lastname: Sloane
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Paige
authors.initials: P
authors.lastname: Sholar
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Taylor
authors.forename: Debra
authors.initials: D
authors.lastname: Berkelhammer
authors.forename: Benjamen D
authors.initials: BD
authors.lastname: Coats
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Jayson
authors.initials: J
authors.lastname: Rieger
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000502:physiology*
chemical_list: C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D010880:Piperidines; D043705:Receptor, Adenosine A2A