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The Journal of Neuroscience, December 24, 2008, 28(52):14087-14096; doi:10.1523/JNEUROSCI.2406-08.2008

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Development/Plasticity/Repair
Activation of the Neuronal Extracellular Signal-Regulated Kinase 2 in the Spinal Cord Dorsal Horn Is Required for Complete Freund's Adjuvant-Induced Pain Hypersensitivity

Qinghao Xu, Sandra M. Garraway, Amanda R. Weyerbacher, Sarah J. Shin, and Charles E. Inturrisi

Departments of Pharmacology and Neuroscience, Weill Cornell Medical College, New York, New York 10065

Correspondence should be addressed to Dr. Charles E. Inturrisi, Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, Room LC-524, New York, NY 10065. Email: ceintur{at}med.cornell.edu

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling in the spinal cord dorsal horn (SCDH) has been implicated in injury-induced pain hypersensitivity. Available ERK pathway inhibitors cannot distinguish between ERK1 and ERK2, nor can they differentially target the expression of neuronal or glial ERK1/2. We selectively inhibited the expression of ERK2 in neurons of the adult mouse SCDH by use of an ERK2 small interfering RNA (siRNA) delivered by a neurotropic adenoassociated viral vector. In situ hybridization revealed a siRNA vector-induced decrease in ERK2 mRNA in the ipsilateral SCDH. Immunohistochemistry showed a decreased neuronal phospho-ERK1/2 (pERK1/2), and Western blot analysis revealed that both ERK2 expression and phosphorylation were reduced by the siRNA vector. In contrast, basal ERK1 expression was not affected, although pERK1 was slightly increased. The siRNA vector-induced knockdown of ERK2 expression in the SCDH did not alter the baseline mechanical or thermal paw withdrawal thresholds. Hindpaw intraplantar injection of complete Freund's adjuvant (CFA) produced peripheral inflammation, mechanical allodynia, and thermal hyperalgesia in vector control animals that persisted for at least 96 h. It also caused an increase in SCDH ERK1 and ERK2 levels at 96 h and pERK1 and pERK2 levels at 1 and 96 h. The ERK2 siRNA vector prevented changes in ERK1, ERK2, and pERK2. In addition, the siRNA vector protected the animals from developing mechanical allodynia and thermal hyperalgesia throughout the 96 h after CFA. These findings indicate that ERK2 in the SCDH neurons is critical for the development of inflammatory pain hypersensitivity.

Key words: ERK2; spatial knockdown; RNAi; inflammatory pain; spinal cord dorsal horn; rAAV vector

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Received May 28, 2008; revised Sept. 9, 2008; accepted Oct. 20, 2008.

Correspondence should be addressed to Dr. Charles E. Inturrisi, Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, Room LC-524, New York, NY 10065. Email: ceintur{at}med.cornell.edu

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