Effects of the selective adenosine A1 receptor agonist 5 '-chloro-5 '-deoxy-N6-(2-endo-norbornyl) adenosine on nociception in mice

Background. To investigate the analgesic effect of 5’-chloro-5’-deoxy-N6-(2-endo-norbornyl)-adenosine (5’Cl5’d-(±)-ENBA), a very selective agonist with subnanomolar affinity for the human A1 adenosine receptor (A1AR), the formalin test was applied in freely moving mice. Methods. The formalin test-induced pain is a widely used animal model of persistent pain. Nociceptive responses are divided into an early, short lasting first phase (0-7 min) caused by a primary afferent discharge produced by the stimulus, followed by a quiescent period and a second, prolonged phase (15-60 min) of tonic pain. The total time of the nociceptive response was measured every 5 min and expressed as the total time of the responses in min (mean SEM). Recording of nociceptive behaviour commenced immediately after the formalin injection and was continued for 60 min. Results. Systematic administration of 5’Cl5’d-(±)-ENBA (1-2 mg/Kg, i.p.), 10 min before formalin reduced the late nocifensive behaviour induced by formalin in a dose-dipendent manner. The higher dose 5’Cl5’d-(±)-ENBA used reduced both the early and the late phases of the formalin test, and this was prevented by the DPCPX (3 mg/Kg, i.p.), a selective A1 receptor antagonist. Conclusion. These data further evidence that the adenosine A1 receptor stimulation results effective in reverting formalin-induced nocifensive behaviour in mice and suggest that the presence of adenosine receptors within the endogenous antinociceptive pathway may play a critical role in pain modulation. Moreover, it was demonstrated that the substitution of 5’-OH group with a chlorine in adenosine derivatives is not detrimental for the antinociceptive effect mediated by A1AR.