THE CAMP TRANSDUCTION CASCADE MEDIATES THE PROSTAGLANDIN E-2 ENHANCEMENT OF THE CAPSAICIN-ELICITED CURRENT IN RAT SENSORY NEURONS - WHOLE-CELL AND SINGLE-CHANNEL STUDIES

Treatment with proinflammatory prostaglandin E-2 (PGE(2)) produced a t ransient sensitization of whole-cell currents elicited by the vanilloi d capsaicin. The intracellular signaling pathways that mediate the ini tiation of this PGE(2)-induced sensitization of the capsaicin-elicited current in rat sensory neurons are not well established. Treatment wi th either forskolin (100 nM to 10 mu M) or membrane-permeant analogs o f cAMP, 8-bromo-cAMP (8-Br-cAMP) and chlorphenylthio-cAMP (10 mu M to 1 mM), transiently sensitized neuronal responses elicited by capsaicin in a manner analogous to that produced by PGE(2). The duration of sen sitization was lengthened with increasing concentrations of forskolin; however, higher concentrations of 8-Br-cAMP or chlorphenylthio-cAMP l ed to a shortening of sensitization. The inactive analog of forskolin, dideoxy-forskolin, had no effect on capsaicin responses. Inclusion of the inhibitor of protein kinase A in the recording pipette completely suppressed the sensitization produced by PGE(2) or forskolin. In reco rdings from membrane patches in the cell-attached configuration, the b ath application of capsaicin evoked single-channel currents in which t he level of channel activity was concentration-dependent and had an EC 50 of 1.4 mu M. These single-channel currents evoked by capsaicin exhi bited an apparent reversal potential of +4 mV and were blocked by the capsaicin antagonist capsazepine. Exposure of the sensory neuron to ei ther PGE(2) or forskolin produced a large and transient increase in th e mean channel activity (NPo) elicited by capsaicin, although the unit ary conductance remained unaltered. Taken together, these observations suggest that modulation of the capsaicin-gated channel by the cAMP-pr otein kinase A signaling pathway enhanced the gating of these channels and consequently resulted in the sensitization of the whole-cell curr ents.