Frequency-Dependent ERK Phosphorylation in Spinal Neurons by Electric Stimulation of the Sciatic Nerve and the Role in Electrophysiological Activity

Abstract

The phosphorylation of extracellular signal-regulated kinase (pERK) in DRG and dorsal horn neurons is induced by the C-fiber electrical stimulation to the peripheral nerve. The present study was designed to investigate the expression and modulation of pERK in the rat dorsal horn neurons produced by repetitive electrical stimulation, and its involvement in the electrophysiological activity of dorsal horn neurons. Electrical stimulation of C-fiber intensity at different frequencies was applied to the sciatic nerve; the stimuli-induced pERK expression and the activity in dorsal horn neurons were studied by immunohistochemistry and extracellular recording, respectively. Electrical stimulation of C-fibers (3 mA) induced pERK expression in dorsal horn neurons in a frequency-dependent manner, indicating that the frequency of electrical stimulation is an important factor which activates the intracellular signal pathway in the spinal cord. To demonstrate the underlying mechanism of this frequency-dependent pERK expression, an NMDA receptor antagonist, MK-801, and a voltage sensitive calcium channel antagonist, nifedipine, were administrated intrathecally before the stimulation. We found that high frequency (0.5 Hz and 10 Hz) but not low frequent (0.05 Hz) stimulus-evoked pERK was partially inhibited by MK-801. Both high and low frequency stimulus-evoked pERK were inhibited by the nifedipine treatment. The extracellular single unit activities were recorded from the laminae I-II and V of the L4-5 dorsal horn, and we found that blockage of the intracellular ERK signal suppressed the wind-up responses in a dose-dependent manner. In contrast, any change in the mechanically evoked responses was not observed following the administration of ERK inhibitor. These observations indicate that ERK activation plays an important role in the induction of the wind-up responses in dorsal horn nociceptive neurons.

Histamine Influences Body Temperature by Acting at H1and H3 Receptors on Distinct Populations of Preoptic Neurons

“…These results point to the possibility that the [Ca] i is a physiological modulator which induces changes in the pERK level as a function of neuronal firing. A similar connection was recently suggested for activity-dependent changes in pERK in DRG neurons (Fukui et al, 2007). …”

The Pain Pathway in the Rat following Noxious Thermal Stimulation: Effect of Morphine on pERK1/2 and TRPV1 at the Dorsal Horn Level, and on Hyperalgesia

“…As has already been shown in other experiments employing a qualitative similar stimulus, the ERK1/2 activation is mainly seen in superficial areas of the dorsal horn [3,15]. Qualitative different nociceptive stimuli to other peripheral tissues have also revealed this same pattern of cell activation in the spinal cord [4,6,16].…”

“…The role played by pERK1/2 in this behavioral sensitization is not clear, but it has been postulated that ERK1/2 phosphorylation can be considered a very specific marker to indicate long-term changes in sensory neurons following nociceptor activation [8,22,23]. Another possible mechanism by which ERK1/2 might modulate neuronal excitability is through direct regulation of membrane ion channels [3]. Nonetheless, we previously found an increased number of pERK1/2-positive cells in the DRG up to 8 h after the heat stimulus reflecting an altered state of C-fiber afferent excitability [2].…”

“…On several instances an increased activation/phosphorylation of ERK1/2 leading to pERK1/2 immunoreactivity in the spinal dorsal horn in response to various nociceptive stimuli has been demonstrated [3,4,5,6]. The signaling molecule pERK1/2 has been regarded as a very powerful tool to follow excitation in nociceptive neurons towards different stimulus intensity, and its gradual response has been linked to the regulation of neuronal excitability [5,7,8].…”

c-Fos or pERK, Which is a Better Marker for Neuronal Activation and Central Sensitization After Noxious Stimulation and Tissue Injury?

“…The degree of pERK suppression by MEK inhibitors can be readily confirmed by checking pERK levels. Using these inhibitors, accumulating evidence shows pERK in dorsal horn neurons is required for the induction of central sensitization, including behavioral indication of central sensitization such as second phase pain response to formalin [15,18] and capsaicin-induced secondary mechanical allodynia [42], and electrophysiological indication of central sensitization such as windup [63] and long-term potentiation in spinal cord neurons [64]. pERK induces central sensitization via increasing the activity of excitatory glutamate receptors (AMPA and NMDA) [65] and suppressing the activity of inhibitory potassium channels (Kv4.2) [66] in dorsal horn neurons (Fig.…”