The cAMP transduction cascade mediates the prostaglandin E sub(2) enhancement of the capsaicin-elicited current in rat sensory neurons: Whole-cell and single-channel studies

• Published in: The Journal of neuroscience 1998-08, Vol.18 (16), p.6081-6092
• Main Authors: Lopshire, J C, Nicol, G D
• Format: Article
• Language: English
• ISSN: 0270-6474

Treatment with proinflammatory prostaglandin E sub(2) (PGE sub(2)) produced a transient sensitization of whole-cell currents elicited by the vanilloid capsaicin. The intracellular signaling pathways that mediate the initiation of this PGE sub(2)-induced sensitization of the capsaicin- elicited current in rat sensory neurons are not well established. Treatment with either forskolin (100 nM to 10 mu M) or membrane-permeant analogs of 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 sub(2). 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 PGE sub(2) 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 EC sub(50) of 1.4 mu M. 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 PGE sub(2) or forskolin produced a large and transient increase in the mean channel activity (NP sub(o)) 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.