Effects of 5'-chloro-5'-deoxy-N6-(±)-endo-norbornyl-adenosine, a potent and highly selective A1 adenosine receptor agonist, on neuropathic pain-induced behavioural and morphological changes in spinal microglia

This study was undertaken in order to investigate the effect of chronic treatment with 5'-chloro-5'-deoxy-N6-(±)-endo-norbornyladenosine (5'Cl5'd-(±)-ENBA),1 a potent and highly selective adenosine A1 receptor agonist, on thermal hyperalgesia and mechanical allodynia in a mouse model of neuropathic pain, the spared nerve injury (SNI). Chronic systemic administrations of 5'Cl5'd-(±)-ENBA (0.5 mg/kg, i.p once a day) reduced both thermal hyperalgesia and mechanical allodynia 3 and 7 days after SNI, in a way prevented by DPCPX (3 mg/kg, i.p.), a selective A1 receptor antagonist. SNI induced spinal changes on microglial activation ipsilaterally to the nerve injury. Moreover, 5'Cl5'd-(±)-ENBA significantly reduced microglial activation in vitro. In particular pre-incubation with 5'Cl5'd-(±)-ENBA prevented the microglial morphological changes induced by LPS, ATP, LPS+ATP challenges. Our results demonstrated an involvement of A1 receptors in the increase of nociceptive thresholds and in spinal changes occurred in neuropathic pain. In addition, 5'Cl5'd-(±)-ENBA antiallodynic and antihyperalgesic effects could be mediated by the A1 receptors expressed on microglial cells. (1) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393-2406.