The cAMP transduction cascade mediates the PGE2-induced inhibition of potassium currents in rat sensory neurones.

Enhanced sensitivity to noxious stimuli is one of the characteristics of the inflammatory response and may result from an increase in the excitability of small-diameter sensory neurones that conduct nociceptive signals. Indeed, a number of pro-inflammatory agents that are synthesized and released in response to trauma can stimulate directly or augment the activation of sensory neurones (Treede et al. 1992). In this regard, prostaglandins represent an important group of agents that sensitize sensory neurones. Exposing various preparations of sensory neurones to prostaglandin E2 (PGE2) or prostaglandin I2 (PGI2) increases the number of action potentials elicited by noxious thermal, chemical and/or mechanical stimuli (Handwerker, 1976; Mense, 1981; Baccaglini & Hogan, 1983; Martin et al. 1987; Nicol & Cui, 1994; Nicol et al. 1997). These prostanoids also facilitate neurotransmitter release evoked by exposing sensory neurones to bradykinin, capsaicin or high extracellular potassium (Franco-Cereceda, 1989; Andreeva & Rang, 1993; Hingtgen & Vasko, 1994; Vasko et al. 1994). Although the cellular mechanisms underlying the actions of these prostaglandins are not well understood, recent evidence suggests that these eicosanoids modulate ion channel activity that could enhance the excitability of sensory neurones. For example, PGE2 increases the amplitude of a tetrodotoxin (TTX)-resistant sodium current in adult and neonatal rat dorsal root ganglion (DRG) cells (Gold et al. 1996a; England et al. 1996). This prostanoid also suppresses a calcium-dependent slow after-hyperpolarization in adult rat nodose ganglia cells and DRG neurones (Fowler et al. 1985; Gold et al. 1996B). Furthermore, we demonstrated recently that PGI2 and PGE2 attenuate whole-cell potassium currents (IK), whereas the non-sensitizing prostanoid PGF2α is ineffective in sensory neurones (Nicol et al. 1997). The question remains as to whether the prostaglandin-induced modulation of ion channels results in sensitization of sensory neurones. To initially address this issue, it is important to assess whether prostaglandin-induced sensitization and alterations in ion channels are mediated by the same transduction mechanisms. Because the sensitizing actions of PGE2 or PGI2 on sensory neurones are mediated by the cyclic AMP (cAMP) transduction cascade (Ferreira & Nakamura, 1979; Taiwo et al. 1989; Hingtgen et al. 1995; Cui & Nicol, 1995), modulatory effects of prostanoids on ion channels regulating membrane excitability should also be dependent on the cAMP pathway. We hypothesize that the sensitizing actions of PGE2 are also mediated by the suppression of IK. This notion is based, in part, on observations wherein cAMP modulates voltage-dependent IK in a variety of cell types. In the GH4C1 pituitary cell line, dibutyryl cAMP suppresses a delayed rectifier IK (Chung & Kaczmarek, 1995). Similarly, the current that arises from the expression of Kv3.2 (delayed rectifier potassium) channels in Chinese hamster ovary cells is inhibited by a membrane-permeant analogue of cAMP (Moreno et al. 1995). Activation of the cAMP pathway in mouse neurones isolated from the colliculus leads to a long-term (2-4 h) enhancement of excitability as exhibited by an increased duration of the action potential and a greater number of action potentials evoked by a depolarizing current pulse (Ansanay et al. 1995). These authors found that stimulation of protein kinase A (PKA) inhibits a delayed rectifier-like IK. Lastly, PGE2, through activation of the cAMP-PKA cascade, may play a role in the regulation of vascular smooth muscle tone. In smooth muscle cells isolated from the tail artery of the rat, PGE2 suppresses a non-inactivating IK (Ren et al. 1996). Therefore, taken together, the sensitivity of excitable cells and its modulation by different mediators will play an important role in the regulation of the physiological function of the cell. To ascertain whether suppression of IK could also be a mechanism for prostaglandin-induced sensitization of sensory neurones, we examined the hypothesis that the cAMP pathway mediates the PGE2-induced decrease in IK in isolated rat embryonic sensory neurones. Our results demonstrate that the cAMP analogue, chlorophenylthio-adenosine cyclic 3′,5′-monophosphate (cpt-cAMP) inhibits a delayed rectifier-like IK in sensory neurones in a manner analogous to PGE2 and that the inhibitory effects of PGE2 on the whole-cell IK are blocked by the inhibition of PKA. Preliminary findings from this study have been reported in abstract form (Evans et al. 1996B).