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Adenosine receptor subtype 3 (A3AR) agonists as novel analgesics in chronic neuropathic pain
Author(s) -
Salvemini Daniela,
Janes Kali,
Finley Amanda,
Doyle Timothy,
Chen Zhoumou,
Bryant Leesa,
Tosh Dilip,
Jacobson Kenneth
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.887.1
Subject(s) - medicine , neuropathic pain , pharmacology , chronic pain , allodynia , hyperalgesia , anesthesia , nociception , receptor , psychiatry
Chronic neuropathic pain is poorly managed and represents a huge unmet medical need. In chronic constriction injury (CCI) and chemotherapy‐induced neuropathic pain (CIPN), we demonstrate the analgesic effects of potent and specific A3AR agonists, IBMECA or Cl‐IBMECA; now in clinical trials as anti‐inflammatory and antitumor agents. In mice and rats with CCI, systemic A3AR agonists reversed mechano‐allodynia in a dose‐dependent manner. These effects were blocked by a selective A3AR antagonist (MRS1523), lost in A3AR −/− mice, and had both peripheral and spinal sites of action that were attenuated by intraplantar or intrathechal injection of MRS1523. CIPN is the major toxicity of widely used antitumoral agents and one of the most common causes of dose reduction and discontinuation of an otherwise life‐saving therapy. In rats, IB‐MECA and Cl‐IB‐MECA blocked or reversed mechano‐allodynia and mechano‐hyperalgesia induced by paclitaxel, oxaliplatin and bortezomib in a dose‐dependent manner without interfering with antitumor effects. The selective and oral A3AR agonists, MRS1898 and MRS5698 were equally effective. Our findings provide the pharmacological rationale towards the clinical development of A3AR agonists for chronic pain of diverse etiologies. Supported by NIH/NIDA [R01 DA024074], NIH/NIHMS [5T32GM008306], Saint Louis University President Research Funds, St. Louis Cancer Center.