Abstract
c-Fos, the protein of the protooncogene c-fos, has been extensively used as a marker for the activation of nociceptive neurons in the spinal cord for more than twenty years since Hunt et al. first reported that peripheral noxious stimulation to a hind paw of rats leads to a marked induction of c-Fos in superficial and deep dorsal horn neurons in 1987. In 1999, Ji et al. reported that phosphorylated extracellular signal-regulated kinase (pERK) is specifically induced by noxious stimulation in superficial dorsal horn neurons. Accumulating evidence indicates that pERK induction or ERK activation in dorsal horn neurons is essential for the development of central sensitization, increased sensitivity of dorsal horn neurons that is responsible for the generation of persistent pain. Further, molecular mechanisms underlying ERK-mediated central sensitization have been revealed. In contrast, direct evidence for c-Fos-mediated central sensitization is not sufficient. After a noxious stimulus (e.g., capsaicin injection) or tissue injury, c-Fos begins to be induced after 30-60 minutes, whereas pERK can be induced within a minute, which can correlate well with the development of pain hypersensitivity. While c-Fos is often induced in the nuclei of neurons, pERK can be induced in different subcellular structures of neurons such as nuclei, cytoplasma, axons, and dendrites. pERK can even be induced in spinal cord microglia and astrocytes after nerve injury. In summary, both c-Fos and pERK can be used as markers for neuronal activation following noxious stimulation and tissue injury, but pERK is much more dynamic and appears to be a better marker for central sensitization.
Highlights
The protooncogene c-fos, can be rapidly induced within minutes by stimulation of a neurotransmitter [1], is called the immediate early gene
We have identified multiple receptors and protein kinases that are involved in phosphorylated extracellular signal-regulated kinase (pERK) induction in dorsal horn neurons [17, 43]
We have demonstrated that morphine and cannabinoid can potently inhibit pERK induction in this model [43]
Summary
The protooncogene c-fos, can be rapidly induced within minutes by stimulation of a neurotransmitter [1], is called the immediate early gene. High-threshold noxious stimuli can induce a very dramatic increase of c-Fos expression in spinal cord dorsal horn neurons. STIMULUS-DEPENDENT EXPRESSION OF C-FOS AND PERK IN SPINAL CORD DORSAL HORN NEURONS. Gao and Ji stimuli, such as light touch, warm water, or A fiber activation normally do not induce the expression of c-Fos and pERK They can be induced in dorsal horn neurons by various types of noxious stimuli, including thermal, mechanical, chemical (e.g., capsaicin, formalin, bee and scorpion venom), and electrical stimuli [5, 7, 20]. After nerve injury, lowintensity stimuli can induce Fos expression [28,29,30] and pERK expression [31, 32] in dorsal horn neurons. A continuous non-noxious input, generated by walking in a rotarod, is able to c-Fos, pERK, and Pain Marker
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