Changes in Osmolality Sensitize the Response to Capsaicin in Trigeminal Sensory Neurons

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Abstract
Changes in tonicity in the peripheral nervous system can activate nociceptors and produce pain. Under local inflammatory conditions the peripheral terminals of nociceptors are subject to deviations from isotonicity. Previously it was shown that several members of the TRP(V) family of ion channels are responsive to changes in tonicity. Here we explore how changes in tonicity affect TRPV1 receptor-mediated responses to capsaicin in dissociated rat trigeminal ganglion (TG) neurons. Using whole cell patch-clamp and calcium imaging, we found that mild anisotonicity (260 and 348 mOsm/kg for hypotonicity and hypertonicity, respectively) strikingly sensitized the capsaicin-evoked current, Icaps. Confocal immunolocalization studies also revealed a modest anisotonicity-mediated redistribution of TRPV1 toward the plasma membrane of TG neurons. With respect to downstream signaling pathways, tonicity-induced sensitization of Icaps was dependent on whether hypo- or hypertonic stimuli were applied. Specifically, antagonism of PKA- and PI3K-activated pathways appreciably reduced the hypertonicity-induced sensitization of Icaps, whereas inhibition of PKC-mediated pathways selectively reduced the sensitization produced by hypotonic solutions. In summary, whereas the overall effects of hypo- and hypertonicity resulted in a similar pattern of potentiation of Icaps, intracellular signaling pathways were selective for hypo- versus hypertonicity-induced tuning of capsaicin-activated currents.