The Role of ERK1/2 Signaling in the Peripheral Nociceptive Circuit

Abstract

ERK1/2 signaling plays a prominent role in the development of chronic pain, yet questions remain concerning the roles of each isoform and the role of their increased activation in disease states, namely in cancer and following inflammation. In order to directly test these questions, experiments utilized both genetic and pharmacological approaches to perturb the ERK1/2 signaling cascade. We find that ERK1 and ERK2 perform both functionally distinct and redundant roles in sensory neurons. Specifically, sensory neuron ERK2 is necessary for cold sensation and the development of inflammatory pain in some preclinical models, while expression of either ERK1 or ERK2 in sensory neurons is necessary for early postnatal maintenance of DRG neuron survival. In light of these results and the plethora of data supporting the role of ERK1/2 signaling in pain, preclinical studies using either a NF1 model or HE3286 treatment yield surprising, negative results. Specifically, in a tumor-free NF1 preclinical model wherein heterozygous loss-of-function of neurofibromin leads to hyper-activation of ERK1/2 signaling, we observe no change in acute, inflammatory, or neuropathic pain as well as no change in acute itch behavior. Similarly, the promising anti-inflammatory therapeutic, HE3286, does not alleviate acute, inflammatory pain despite its known ability to inhibit ERK1/2 signaling, suggesting that this compound is not a suitable analgesic for such acute conditions. While these results do not clearly depict a simple, cohesive role of ERK1/2 signaling in pain, the data reveal and remind one about the complexity of the neurobiology of pain.

Committee Chair

Robert W Gereau

Committee Members

Yu-Qing Cao, Valeria Cavalli, Zhou-Feng Chen, Kelly Monk

Comments

Permanent URL: https://doi.org/10.7936/K7RV0KTG

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

Winter 12-15-2014

Language

English (en)

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