title: Controlling murine and rat chronic pain through A3 adenosine receptor activation.
abstract: 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-dependently 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.
authors.affiliation: Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA.
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Kali
authors.initials: K
authors.lastname: Janes
authors.forename: Collin
authors.initials: C
authors.lastname: Chen
authors.forename: Tim
authors.initials: T
authors.lastname: Doyle
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D058909:Adenosine A3 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D002908:Chronic Disease; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D059408:Pain Management / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test
chemical_list: D058909:Adenosine A3 Receptor Agonists