Sustained reversal of central neuropathic pain induced by a single intrathecal injection of adenosine A 2A receptor agonists

• Published in: Brain, behavior, and immunity behavior, and immunity, 2018-03, Vol.69, p.470-479
• Main Authors: Kwilasz, Andrew J, Ellis, Amanda, Wieseler, Julie, Loram, Lisa, Favret, Jacob, McFadden, Andrew, Springer, Kendra, Falci, Scott, Rieger, Jayson, Maier, Steven F, Watkins, Linda R
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - therapeutic use; Adenosine A2 Receptor Agonists - therapeutic use; Animals; Antibodies, Neutralizing - pharmacology; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Hyperalgesia - physiopathology; Interleukin-10 - immunology; Male; Neuralgia - drug therapy; Neuralgia - etiology; Neuralgia - physiopathology; Phenethylamines - therapeutic use; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries - complications; Spinal Cord Injuries - physiopathology
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.01.005

Central neuropathic pain is a debilitating outcome of spinal cord injury (SCI) and current treatments to alleviate this pain condition are ineffective. A growing body of literature suggests that activating adenosine A receptors (A Rs) decreases the production of proinflammatory cytokines and increases the production of anti-inflammatory cytokines. Here, the effect of administering intrathecal A R agonists on central neuropathic pain was measured using hindpaw mechanical allodynia in a rat model of SCI termed spinal neuropathic avulsion pain (SNAP). Other models of SCI cause extensive damage to the spinal cord, resulting in paralysis and health problems. SNAP rats with unilateral low thoracic (T13)/high lumbar (L1) dorsal root avulsion develop below-level bilateral allodynia, without concomitant motor or health problems. A single intrathecal injection of the A R agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680) reversed SCI-induced allodynia for at least 6 weeks. The reversal is likely in part mediated by interleukin (IL)-10, as intrathecally administering neutralizing IL-10 antibodies 1 week after CGS21680 abolished the anti-allodynic effect of CGS21680. Dorsal spinal cord tissue from the ipsilateral site of SCI (T13/L1) was assayed 1 and 6 weeks after CGS21680 for IL-10, CD11b, and tumor necrosis factor (TNF) gene expression. CGS21680 treatment did not change IL-10 gene expression but did significantly decrease CD11b and TNF gene expression at both timepoints. A second A R agonist, 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), was also able to significantly prevent and reverse SCI-induced allodynia for several weeks after a single intrathecal injection, providing converging lines of evidence of A R involvement. The enduring pain reversal after a single intrathecal injection of A R agonists suggests that A R agonists could be exciting new candidates for treating SCI-induced central neuropathic pain.