Controlling murine and rat chronic pain through A3 adenosine receptor activation
| Autor: | Kenneth A. Jacobson, Dilip K. Tosh, Leesa Bryant, Kali Janes, Zhoumou Chen, Daniela Salvemini, Collin L. Chen, Timothy M. Doyle |
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| Rok vydání: | 2012 |
| Předmět: |
Agonist
Male medicine.medical_specialty Gabapentin medicine.drug_class (+)-Naloxone Pharmacology Biochemistry Research Communications Rats Sprague-Dawley Mice Opioid receptor Adenosine A3 Receptor Agonists Internal medicine Genetics medicine Animals Pain Management Amitriptyline Molecular Biology business.industry Chronic pain medicine.disease Rats Endocrinology Rotarod Performance Test Neuropathic pain Chronic Disease Neuralgia business Biotechnology medicine.drug |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 26(5) |
| ISSN: | 1530-6860 |
| Popis: | Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A3 adenosine receptor (A3AR) 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 A3AR 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. A3AR agonist effects were blocked with A3AR antagonist MRS1523, but not with A1AR (DPCPX) or A2AAR (SCH-442416) antagonists. Our findings provide the scientific rationale and pharmacological basis for therapeutic development of A3AR 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 A3 adenosine receptor activation. |
| Databáze: | OpenAIRE |
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