2'-C-Methyl-2-chloro-N6-cyclopentyladenosine, a potent and highly selective A1 adenosine receptor agonist, has antinociceptive activity and modulates RVM on-and-off cell activities

The study was undetaken to investigate the effect of 2'-C-methyl-2-chloro-N6-cyclopentyladenosine (2'-Me-CCPA), a potent and highly selective A1 adenosine receptor agonist [1], on antinociceptive responses and on spontaneous activity of ON- and OFF-neurons of rostral ventromedial medulla (RVM). Moreover, we investigate whether the intra-periaqueductal grey (PAG) microinjection of 2'-Me-CCPA induced changes in the tail flick latencies, as well as tail-related changes in RVM cell activities. Systemic administrations of 2'-Me-CCPA (2-5 mg/Kg, i.p.), 10 min before formalin, reduced tha late hyperalgesic phase; in formalin test, these effecs were prevented by DPCPX (3 mg/Kg, i.p.), a A1 receptor antagonist, but not by DPMX (3 mg/Kg, i.p.), a A2 receptor antagonist. Intra-PAG microinjections of 2'-Me-CCPA (0.5-1 nmol/rat) increased the tail flick latencies, delayed the tail flick-related onset to ON-cell burst and decreased the duration of OFF-cell ongoing activities, in a dose-dependent manner. These electrophysiological effects were prevented by DPCPX (1 nmol/rat). In cocnlusion, this study confirms the role of A1 receptors in the modulation of inflammatory pain and suggests a critical role of PAG purinergic system for the control of acute and chronic pain. [1] Cappellacci L et al J Med Chem 48, 1550-1562, 2005