Controlling murine and rat chronic pain through A 3 adenosine receptor activation

Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A 3 adenosine receptor (A 3 AR) agonism as a new target‐based therapeutic strategy. The development of mechanoallodynia in a well‐characterized mouse model of neuropathic pain following chronic constriction injury of the sciatic nerve was rapidly and dose‐depend‐ently reversed by the A 3 AR agonists: IB‐MECA, its 2‐chlorinated analog (Cl‐IB‐MECA), and the structurally distinct MRS1898. These effects were naloxone insensitive and thus are not opioid receptor mediated. IB‐MECA was ≥1.6‐fold more efficacious than morphine and >5‐fold more potent. In addition, IB‐MECA was equally efficacious as gabapentin (Neurontin) or amitriptyline, but respectively >350‐ and >75‐fold more potent. Besides its potent standalone ability to reverse established mechanoallodynia, IB‐MECA significantly increased the antiallodynic effects of all 3 analgesics. Moreover, neuropathic pain development in rats caused by widely used chemotherapeutics in the taxane (paclitaxel), platinum‐complex (oxaliplatin), and proteasome‐inhibitor (bortezomib) classes was blocked by IB‐MECA without antagonizing their antitumor effect. A 3 AR agonist effects were blocked with A 3 AR antagonist MRS1523, but not with A 1 AR (DPCPX) or A 2A AR (SCH‐442416) antagonists. Our findings provide the scientific rationale and pharmacological basis for therapeutic development of A 3 AR agonists for chronic pain.—Chen, Z., Janes, K., Chen, C., Doyle, T., Bryant, L., Tosh, D.K., Jacobson, K.A., Salvemini, D. Controlling murine and rat chronic pain through A 3 adenosine receptor activation. FASEB J. 26, 1855‐1865 (2012). www.fasebj.org