Phosphorylation of Extracellular Signal-Regulated Kinase in Primary Afferent Neurons by Noxious Stimuli and Its Involvement in Peripheral Sensitization

Abstract

Alteration in the intracellular signal transduction pathway in primary afferent neurons may contribute to pain hypersensitivity. We demonstrated that very rapid phosphorylation of extracellular signal-regulated protein kinases (pERK) occurred in DRG neurons that were taking part in the transmission of various noxious signals. The electrical stimulation of Adelta fibers induced pERK primarily in neurons with myelinated fibers. c-Fiber activation by capsaicin injection induced pERK in small neurons with unmyelinated fibers containing vanilloid receptor-1 (VR-1), suggesting that pERK labeling in DRG neurons is modality specific. Electrical stimulation at the c-fiber level with different intensities and frequencies revealed that phosphorylation of ERK is dependent on the frequency. We examined the pERK in the DRG after application of natural noxious stimuli and found a stimulus intensity-dependent increase in labeled cell size and in the number of activated neurons in the c- and Adelta-fiber population. Immunohistochemical double labeling with phosphorylated ERK/VR-1 and pharmacological study demonstrated that noxious heat stimulation induced pERK in primary afferents in a VR-1-dependent manner. Capsaicin injection into the skin also increased pERK labeling significantly in peripheral fibers and terminals in the skin, which was prevented by a mitogen-activated protein kinase/ERK kinase inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminopheylthio)butadiene (U0126). Behavioral experiments showed that U0126 dose-dependently attenuated thermal hyperalgesia after capsaicin injection and suggested that the activation of ERK pathways in primary afferent neurons is involved in the sensitization of primary afferent neurons. Thus, pERK in primary afferents by noxious stimulation in vivo showed distinct characteristics of expression and may be correlated with the functional activity of primary afferent neurons.

Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons

“…Previous reports have suggested that inflammatory and neuropathic pain increases pERK in DRG neurons and that activation of the ERK pathway is involved in peripheral sensitization following noxious stimulation [58][59][60]. In our experiment, α, β-MeATP applied to the axon terminal for 30 min was able to increase the level of pERK as well as the depolarization-induced Ca 2+ influx in the cell bodies.…”

Phosphatidylinositol 3-Kinase Activates ERK in Primary Sensory Neurons and Mediates Inflammatory Heat Hyperalgesia through TRPV1 Sensitization

“…Intradermal capsaicin also induced pERK in epidermal nerve fibers (Fig. 2h,i) and induces pERK in small-sized neurons in the DRG (Dai et al, 2002).…”

“…PKA and PKC appear to regulate hyperalgesia through phosphorylation and activation of TRPV1 (Premkumar and Ahern, 2000;Bhave et al, 2002) and Na V 1.8/1.9 (Gold et al, 1998;McCleskey and Gold, 1999;Julius and Basbaum, 2001;Bhave and Gereau, 2003). ERK (extracellular signal-regulated protein kinase), a member of the MAPK (mitogen-activated protein kinase) family, is activated in primary sensory neurons and epidermal nerve fibers after peripheral inflammation and contributes to inflammatory pain (Aley et al, 2001;Dai et al, 2002;Dina et al, 2003;Ji, 2003).…”

Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2

“…For instance, propentofylline, a glial modulating agent, attenuates nerve-injury-induced mechanical allodynia at doses that inhibit both spinal microglial and astrocytic activation (28). Very little information is available regarding the intracellular signal transduction mechanisms occurring in glial cells activated during chronic pain, but recent papers provide evidence that MAP kinases play a critical role (29)(30)(31). Activation of the p38 pathway plays an essential role in production of proinflammatory cytokines such as IL-1␤, TNF-␣, and IL-6, and induction of enzymes (cyclooxygenase-2, iNOS) (32).…”