Specific Involvement of PKC-ε in Sensitization of the Neuronal Response to Painful Heat

Abstract

Pain is unique among sensations in that the perceived intensity increases, or sensitizes, during exposure to a strong stimulus. One important mediator of sensitization is bradykinin (BK), a peptide released as a consequence of tissue damage. BK enhances the membrane ionic current activated by heat in nociceptive neurons, using a pathway that involves activation of protein kinase C (PKC). We find that five PKC isoforms are present in sensory neurons but that only PKC-epsilon is translocated to the cell membrane by BK. The heat response is sensitized when constitutively active PKC-epsilon is incorporated into nociceptive neurons. Conversely, BK-induced sensitization is suppressed by a specific peptide inhibitor of PKC-epsilon. We conclude that PKC-epsilon is principally responsible for sensitization of the heat response in nociceptors by bradykinin.

Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1

“…TRPV1 is acknowledged to exist in peripheral nerve terminals and can be sensitized by noxious heat over 43 °C. Additionally, some evidence also validates the contribution of TRPV1 to mechanotransmission after injuries in different conditions [42][43][44] .…”

“…The function of TRPV1 is augmented by many endogenous mediators following direct PKCε activation [15] . Specifically, the phosphorylation and activation of PKCε intensifies the responses of sensory neurons to noxious heat [16] . Previous studies have demonstrated that PKCε activation in small-and medium-sized DRG neurons alters the TRPV1 function and consequently leads to hyperalgesia.…”

The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity

“…UTP activates the P2Y purinergic GPCR, which is also coupled to PKC-. PKC-induces sensitization of nociceptors via changes in TRPV1 (Cesare et al, 1999) and contributes to inflammatory hyperalgesia (Hucho et al, 2005). PKC activators increase TTXr-Per current in rat and mouse DRG neurons (Baker, 2005) so that its sensitizing actions are likely to be attributable to changes in TRP and voltage-gated sodium channels.…”

“…Inflammatory mediators, including amines, prostanoids, kinins, purines, protons, and nerve growth factor (NGF), sensitize the nociceptor peripheral terminal by producing a reduction in the threshold of transducer channels (McCleskey and Gold, 1999;Julius and Basbaum, 2001), an increase in terminal membrane excitability (Amir et al, 2006), and insertion of receptors into the terminal membrane (Zhang et al, 2005). The high threshold of the transducers are reduced by posttranslational processing in response to activation by the inflammatory mediators of multiple intracellular signaling pathways [PKA, PKC, extracellular signalregulated kinase, phosphatidylinositol 3 (PI3) kinase, and phospholipase C] (Cesare et al, 1999;Aley et al, 2001;Bautista et al, 2006). Prostaglandin E 2 (PGE 2 ), 5-HT, and bradykinin (BK) increase the Na v 1.8-like TTXr current in DRG neurons, with an increase in amplitude and rates of activation and inactivation (Gold et al, 1996(Gold et al, , 1998England et al, 2001).…”

Stimulation of the neurokinin 3 receptor activates protein kinase Cε and protein kinase D in enteric neurons

“…PKD, together with PKCε, can phosphorylate the transient receptor potential/vanilloid channel of nociceptive neurons, resulting in hyperalgesia to thermal stimuli (5,53). A similar role of PKD in controlling IPAN excitability is of particular interest, since this kinase is capable of sustained activation and of amplifying receptor-mediated signals (26).…”