Abstract
We examined whether nerve growth factor (NGF), an inflammatory mediator that contributes to chronic hypersensitivity, alters the intracellular signaling that mediates the sensitizing actions of PGE2 from activation of protein kinase A (PKA) to exchange proteins directly activated by cAMP (Epacs). When isolated sensory neurons are grown in the absence of added NGF, but not in cultures grown with 30 ng/ml NGF, inhibiting protein kinase A (PKA) activity blocks the ability of PGE2 to augment capsaicin-evoked release of the neuropeptide CGRP and to increase the number of action potentials (APs) evoked by a ramp of current. Growing sensory neurons in culture in the presence of increasing concentrations of NGF increases the expression of Epac2, but not Epac1. An intradermal injection of complete Freund's adjuvant into the rat hindpaw also increases the expression of Epac2, but not Epac1 in the dorsal root ganglia and spinal cord: an effect blocked by intraplantar administration of NGF antibodies. Treating cultures grown in the presence of 30 ng/ml NGF with Epac1siRNA significantly reduced the expression of Epac1, but not Epac2, and did not block the ability of PGE2 to augment capsaicin-evoked release of CGRP from sensory neurons. Exposing neuronal cultures grown in NGF to Epac2siRNAreduced the expression of Epac2, but not Epac1 and prevented the PGE2-induced augmentation of capsaicin and potassium-evoked CGRP release in sensory neurons and the PGE2-induced increase in the number of APs generated by a ramp of current. In neurons grown with no added NGF, Epac siRNAs did not attenuate PGE2-induced sensitization. These results demonstrate that NGF, through increasing Epac2 expression, alters the signaling cascade that mediates PGE2-induced sensitization of sensory neurons, thus providing a novel mechanism for maintaining PGE2-induced hypersensitivity during inflammation.
Highlights
A major component of the hypersensitivity that occurs with tissue injury and inflammation results from an increase in the excitability of small diameter sensory neurons that communicate noxious sensations to the spinal cord
Prostaglandin-induced sensitization of sensory neurons grown in the absence, but not the presence of nerve growth factor (NGF) is mediated by activation of protein kinase A (PKA) Previous studies showed that sensitization of sensory neurons by acute exposure to PGE2 or PGI2 was mediated by activation of the cAMP transduction cascade [11,12,15,45]
In contrast to neurons grown in the absence of NGF, when cells were grown in 30 ng/ml NGF, the PGE2-induced increase in capsaicinevoked release was not blocked by pretreatment with 10 mM H-89 (Fig. 1B)
Summary
A major component of the hypersensitivity that occurs with tissue injury and inflammation results from an increase in the excitability of small diameter sensory neurons that communicate noxious sensations to the spinal cord. This phenomenon, termed peripheral sensitization, is mediated largely by proinflammatory prostaglandins which directly activate specific G protein-coupled receptors (GPCRs) and their associated signaling pathways in sensory neurons [1,2,3,4,5]. During inflammation or after repeated exposure to PGE2, the sensitizing actions of this prostanoid are maintained and/or prolonged and are not blocked by PKA inhibitors [13,16,17,18]. During prolonged PGE2-induced hyperalgesia, the early phase is attenuated by inhibition of PKA, whereas the later phase is blocked by PKC inhibition [14]
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