Phosphorothioate oligodeoxynucleotides can selectively alter neuronal activity in the cochlea

A growing body of evidence indicates that extracellular adenosine triphosph ate (ATP) may have a major role in cochlear function. Antagonists of ionotr opic ATP receptors (P2X(2)) have significant effects on cochlear potentials and distortion product otoacoustic emissions (DPOAEs). We tested whether a ntisense oligodeoxynucleotides (ODNs) would mimic the functional deficienci es induced by the ATP antagonists through binding to P2X(2) ATP receptor mR NA and thereby reduce the number of ATP receptors expressed in the membrane of the cells. Both a phosphorothioate ODN (S-ODN) antisense and a phosphod iester ODN (P-ODN) antisense to the P2X(2) sequence and random sense ODNs c ontaining 21 nucleotides were administered chronically (7 days) to the guin ea pig cochlea via the perilymph compartment. Sound evoked cochlear potenti als (cochlear microphonic; summating potential; compound action potential o f the auditory nerve, CAP; latency of the first negative peak in the CAP, N 1 latency) and DPOAEs were monitored to assess the effects of the ODNs. Res ults indicate that the phosphorothioate derivatives of both the antisense a nd random sense ODNs suppressed the CAP and prolonged the N1 latency with n o significant effect on the other parameters. The P-ODNs had no effect. Sin ce both the antisense and random sense S-ODNs had the same effect, we concl ude that the S-ODNs affected neuronal function in a manner that did not inv olve binding to the ATP receptor mRNA. (C) 1999 Elsevier Science B.V. All r ights reserved.