Inosine Reduces Pain-Related Behavior in Mice: Involvement of Adenosine A1 and A2A Receptor Subtypes and Protein Kinase C Pathways

• Published in: The Journal of pharmacology and experimental therapeutics 2010-08, Vol.334 (2), p.590-598
• Main Authors: Nascimento, Francisney P., Figueredo, Sonia M., Marcon, Rodrigo, Martins, Daniel F., Macedo, Sérgio J., Lima, Denise A.N., Almeida, Rúbia C., Ostroski, Rosana M., Rodrigues, Ana Lúcia S., Santos, Adair Roberto Soares
• Format: Article
• Language: English
• Subjects: Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Animals; Chronic Disease; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Inflammation - metabolism; Inflammation - physiopathology; Inosine - physiology; Male; Mice; Motor Activity; Pain - etiology; Pain - metabolism; Pain - physiopathology; Pain Measurement; Peripheral Nervous System Diseases - metabolism; Peripheral Nervous System Diseases - physiopathology; Protein Kinase C - physiology; Rats; Rats, Wistar; Receptor, Adenosine A1 - physiology; Receptor, Adenosine A2A - physiology; Receptor, Adenosine A3 - physiology; Signal Transduction
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.166058

Inosine, an endogenous purine, is the first metabolite of adenosine in a reaction catalyzed by adenosine deaminase. This study aimed to investigate the antinociceptive effects of inosine against several models of pain in mice and rats. In mice, inosine given by systemic or central routes inhibited acetic acid-induced nociception. Furthermore, inosine also decreased the late phase of formalin-induced licking and the nociception induced by glutamate. Inosine produced inhibition (for up to 4 h) of mechanical allodynia induced by complete Freund's adjuvant (CFA) injected into the mouse's paw. Given chronically for 21 days, inosine reversed the mechanical allodynia caused by CFA. Moreover, inosine also reduced the thermal (cold stimuli) and mechanical allodynia caused by partial sciatic nerve ligation (PSNL) for 4 h; when inosine was chronically administered, it decreased the mechanical allodynia induced by PSNL for 22 days. Antinociception caused by inosine in the acetic acid test was attenuated by treatment of mice with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A1 receptor antagonist), 8-phenyltheophylline (8-PT; a nonselective adenosine A1 receptor antagonist), and 4-{2- [7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl- amino]ethyl}phenol (ZM241385; a selective adenosine A2A receptor antagonist). In rats, inosine inhibited the mechanical and heat hyperalgesia induced by bradykinin and phorbol 12-myristate 13-acetate, without affecting similar responses caused by prostaglandin E2 or forskolin. These results indicate that inosine induces antinociceptive, antiallodynic, and antihyperalgesic effects in rodents. The precise mechanisms through which inosine produces antinociception are currently under investigation, but involvement of adenosine A1 and A2A receptors and blockade of the protein kinase C pathway seem to largely account for inosine's antinociceptive effect.