Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models

Benedict J. Alter, Chengshui Zhao, Farzana Karim, Gary E. Landreth, Robert W. Gereau IV

Research output: Contribution to journalArticle

Abstract

The extracellular signal-regulated kinase (ERK) isoforms, ERK1 and ERK2, are believed to be key signaling molecules in nociception and nociceptive sensitization. Studies using inhibitors targeting the shared ERK1/2 upstream activator, mitogen-activated protein kinase kinase (MEK), and transgenic mice expressing a dominant-negative form of MEK have established the importance of ERK1/2 signaling. However, these techniques do not discriminate between ERK1 and ERK2. To dissect the function of each isoform in pain, we used mice with a targeted genetic deletion of ERK1 [ERK1 knock-out (KO)] to test the hypothesis that ERK1 is required for behavioral sensitization in rodent pain models. Despite activation (phosphorylation) of ERK1 after acute noxious stimulation and in models of chronic pain, we found that ERK1 was not required for formalin-induced spontaneous behaviors, complete Freund's adjuvant-induced heat and mechanical hypersensitivity, and spared nerve injury-induced mechanical hypersensitivity. However, ERK1 deletion did delay formalin-induced long-term heat hypersensitivity, without affecting formalin-induced mechanical hypersensitivity, suggesting that ERK1 partially shapes long-term responses to formalin. Interestingly, ERK1 deletion resulted in elevated basal ERK2 phosphorylation. However, this did not appear to influence nociceptive processing, since inflammation-induced ERK2 phosphorylation and pERK1/2 immunoreactivity in spinal cord were not elevated in ERK1 KO mice. Additionally, systemic MEK inhibition with SL327 (α-[amino[(4-aminophenyl)thio] methylene]-2-(trifluoromethyl)benzeneacetonitrile) attenuated formalin-induced spontaneous behaviors similarly in wild-type and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1. Together, these results suggest that ERK1 plays a limited role in nociceptive sensitization and support a predominant role for ERK2 in these processes.

Original languageEnglish (US)
Pages (from-to)11537-11547
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number34
DOIs
StatePublished - Aug 25 2010
Externally publishedYes

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Formaldehyde
Mitogen-Activated Protein Kinase Kinases
Hypersensitivity
Pain
Phosphorylation
Knockout Mice
Protein Isoforms
Hot Temperature
Nociception
Freund's Adjuvant
Extracellular Signal-Regulated MAP Kinases
Chronic Pain
Transgenic Mice
Rodentia
Spinal Cord
Inflammation
Wounds and Injuries

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models. / Alter, Benedict J.; Zhao, Chengshui; Karim, Farzana; Landreth, Gary E.; Gereau IV, Robert W.

In: Journal of Neuroscience, Vol. 30, No. 34, 25.08.2010, p. 11537-11547.

Research output: Contribution to journalArticle

Alter, Benedict J. ; Zhao, Chengshui ; Karim, Farzana ; Landreth, Gary E. ; Gereau IV, Robert W. / Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 34. pp. 11537-11547.
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