Covalently Binding Adenosine A 3 Receptor Agonist ICBM Irreversibly Reduces Voltage-Gated Ca 2+ Currents in Dorsal Root Ganglion Neurons.

Interest has been focused in recent years on the analgesic effects exerted by adenosine and its receptors, A 1 , A 2A , A 2B , and A 3 adenosine receptor (AR) subtypes, in different in vivo models of chronic pain. In particular, it was demonstrated that selective A 3 AR agonists reduced pro-nociceptive N-type Ca 2+ channels in dorsal root ganglion (DRG) neurons isolated from rats and, by this mechanism, inhibit post inflammatory visceral hypersensitivity. In the present study, we investigate the effect of a previously reported irreversibly binding A 3 AR agonist, ICBM, on Ca 2+ currents (I Ca ) in rat DRG neurons. Present data demonstrate that ICBM, an isothiocyanate derivative designed for covalent binding to the receptor, concentration-dependently inhibits I Ca . This effect is irreversible, since it persists after drug removal, differently from the prototypical A 3 AR agonist, Cl-IB-MECA. ICBM pre-exposure inhibits the effect of a subsequent Cl-IB-MECA application. Thus, covalent A 3 AR agonists such as ICBM may represent an innovative, beneficial, and longer-lasting strategy to achieve efficacious chronic pain control versus commonly used, reversible, A 3 AR agonists. However, the possible limitations of this drug and other covalent drugs may be, for example, a characteristic adverse effect profile, suggesting that more pre-clinical studies are needed.