Title

 

Authors

L. Luongo, F. Guida, C. Giordano, D. Siniscalco, L. Gatta, E. Palazzo, V. de Novellis, F. Rossi, S. Maione.

Department of Experimental Medicine, Pharmacology Division, The Second University of Naples

 

Abstract

This study was undertaken in order to investigate the effect of chronic treatment with 5′-chloro-5′-deoxy-(±)-ENBA, a potent and highly selective agonist of human adenosine A1 receptor, on thermal hyperalgesia and mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain in the mouse. Moreover, the role of adenosine A1 receptor on microglial cells in vivo and in vitro has been also investigated. Chronic systemic administrations of 5′-chloro-5′-deoxy-(±)-ENBA (0.5 mg/kg, i.p) reduced both mechanical allodynia and thermal hyperalgesia 3 and 7 days post-SNI, in a way prevented by DPCPX (3 mg/kg, i.p.), a selective A1 receptor antagonist, without exerts any significant changes on the motor coordination or arterial blood pressure. In addition, a single intraperitoneal injection of 5′-chloro-5′-deoxy-(±)-ENBA (0.5 mg/kg, i.p) 7 days post-SNI also reduced both symptoms for at least two hours.  SNI was associated with spinal changes in microglial activation ipsilaterally to the nerve injury.  Activated hypertrophic microglia was significantly reduced by the 5′-chloro-5′-deoxy-(±)-ENBA chronic treatment. To demonstrate a possible direct effect on the microglial A1 adenosine receptor we have evaluated its expression on microglia cell cultures treated with several challenges to reproduce, at least in part, the local “pro-inflammatory” microenvironment generated by the increased nociceptive transmission in the dorsal horn of spinal cord following SNI. We have also evaluated the effect of 5′-chloro-5′-deoxy-(±)-ENBA on the microglia morphological changes in the same conditions. This study shows an involvement of A1 receptor in the the spinal microglial changes which occur in neuropathic pain. Moreover, the present study demonstrates that 5′-chloro-5′-deoxy-(±)-ENBA does not affect motor coordination or blood pressure.