The cAMP Transduction Cascade Mediates the Prostaglandin E2Enhancement of the Capsaicin-Elicited Current in Rat Sensory Neurons: Whole-Cell and Single-Channel Studies

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Abstract
Treatment with proinflammatory prostaglandin E2(PGE2) produced a transient sensitization of whole-cell currents elicited by the vanilloid capsaicin. The intracellular signaling pathways that mediate the initiation of this PGE2-induced sensitization of the capsaicin-elicited current in rat sensory neurons are not well established. Treatment with either forskolin (100 nm to 10 μm) or membrane-permeant analogs of cAMP, 8-bromo-cAMP (8-Br-cAMP) and chlorphenylthio-cAMP (10 μm to 1 mm), transiently sensitized neuronal responses elicited by capsaicin in a manner analogous to that produced by PGE2. The duration of sensitization was lengthened with increasing concentrations of forskolin; however, higher concentrations of 8-Br-cAMP or chlorphenylthio-cAMP led 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 PGE2 or forskolin. In recordings from membrane patches in the cell-attached configuration, the bath application of capsaicin evoked single-channel currents in which the level of channel activity was concentration-dependent and had an EC50 of 1.4 μm. These single-channel currents evoked by capsaicin exhibited an apparent reversal potential of +4 mV and were blocked by the capsaicin antagonist capsazepine. Exposure of the sensory neuron to either PGE2 or forskolin produced a large and transient increase in the mean channel activity (NPo) elicited by capsaicin, although the unitary conductance remained unaltered. Taken together, these observations suggest that modulation of the capsaicin-gated channel by the cAMP–protein kinase A signaling pathway enhanced the gating of these channels and consequently resulted in the sensitization of the whole-cell currents.