Extracellular signal-regulated kinase (ERK) activation is required for itch sensation in the spinal cord.
BACKGROUND
Itch, chronic itch in particular, can have a significant negative impact on an individual's quality of life. However, the molecular mechanisms underlying itch processing in the central nervous system remain largely unknown.


RESULTS
We report here that activation of ERK signaling in the spinal cord is required for itch sensation. ERK activation, as revealed by anti-phosphorylated ERK1/2 immunostaining, is observed in the spinal dorsal horn of mice treated with intradermal injections of histamine and compound 48/80 but not chloroquine or SLIGRL-NH2, indicating that ERK activation only occurs in histamine-dependent acute itch. In addition, ERK activation is also observed in 2, 4-dinitrofluorobenzene (DNFB)-induced itch. Consistently, intrathecal administration of the ERK phosphorylation inhibitor U0126 dramatically reduces the scratching behaviors induced by histamine and DNFB, but not by chloroquine. Furthermore, administration of the histamine receptor H1 antagonist chlorpheniramine decreases the scratching behaviors and ERK activation induced by histamine, but has no effect on DNFB-induced itch responses. Finally, the patch-clamp recording shows that in histamine-, chloroquine- and DNFB-treated mice the spontaneous excitatory postsynaptic current (sEPSC) of dorsal horn neurons is increased, and the decrease of action potential threshold is largely prevented by bathing of U0126 in histamine- and DNFB-treated mice but not those treated with chloroquine.


CONCLUSIONS
Our results demonstrate a critical role for ERK activation in itch sensation at the spinal level.
Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. lzhang0808@tongji.edu.cn.
Ling
L
Zhang
Guan-Yu
GY
Jiang
Ning-Jing
NJ
Song
Ying
Y
Huang
Jia-Yin
JY
Chen
Qing-Xiu
QX
Wang
Yu-Qiang
YQ
Ding
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002738:Chloroquine; D004139:Dinitrofluorobenzene; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006632:Histamine; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D009842:Oligopeptides; D010766:Phosphorylation / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects / Q000201:enzymology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011537:Pruritus / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D011969:Receptors, Histamine H1 / Q000378:metabolism; D012677:Sensation / Q000187:drug effects; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors
D002070:Butadienes; D009570:Nitriles; D009842:Oligopeptides; D016760:Proto-Oncogene Proteins c-fos; D011969:Receptors, Histamine H1; C113580:U 0126; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D006632:Histamine; D002738:Chloroquine; D004139:Dinitrofluorobenzene; D048049:Extracellular Signal-Regulated MAP Kinases