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 A2A receptors (A2ARs) decreases the production of proinflammatory
cytokines and increases the production of anti-inflammatory
cytokines. Here, the effect of administering intrathecal A2AR 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 A2AR 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 A2AR 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 A2AR involvement. The enduring
pain reversal after a single
intrathecal injection of A2AR agonists suggests that A2AR agonists could be exciting new candidates for treating SCI-induced central
neuropathic pain.