The role of intracellular signaling pathways on mu-opioid receptor agonist induced antinociception and tolerance development

Erin Bobeck

Mu-opioid receptor (MOPr) agonists, such as morphine and fentanyl, are the most commonly prescribed drugs to alleviate severe and chronic pain. Although all agonists produce antinociception, they vary in terms of activation of intracellular signaling cascades and tolerance development. Morphine produces little receptor desensitization, β-arrestin recruitment, and receptor internalization, whereas DAMGO and fentanyl produce rapid and robust MOPr desensitization and internalization. Intracellular signaling pathways can be activated by G-protein activation or β-arrestin signaling. Therefore, agonists that cause receptor internalization may lead to activation of different pathways than agonists that strictly use G-protein dependent signaling. Extracellular regulated kinase 1 and 2 (ERK1/2) is a known downstream messenger of β-arrestin. The purpose of the studies in this dissertation was to evaluate the behavioral effects of ligand-biased signaling pathways. Microinjections directly into the ventrolateral periaqueductal gray (vlPAG) allowed for direct manipulation of proteins within the descending pain modulation pathway. It was determined that G-protein or internalization pathways appear to contribute to antinociception depending on the MOPr agonist. Morphine uses a predominately G-protein pathway, whereas DAMGO can use G-protein or internalization mechanisms. Surprisingly, fentanyl seemed to produce antinociception independent of either pathway. These differences were consistent with proposed differences in activation of intracellular signaling cascades, including ERK1/2. Therefore, evaluation of the role of ERK1/2 on antinociception and tolerance was investigated. ERK1/2 was activated following vlPAG microinjection of DAMGO, but not fentanyl, and ERK1/2 inhibition led to attenuation of DAMGO antinociception. Moreover, both the development and expression of tolerance to DAMGO was reversed by inhibition of ERK1/2, but there was no effect of ERK1/2 inhibition on fentanyl tolerance. Although tolerance develops to repeated morphine, DAMGO, or fentanyl microinjections into the vlPAG, the current studies showed that cross-tolerance does not develop between these drugs. This finding suggests that different tolerance mechanisms are engaged by different MOPr agonists and that ERK1/2 plays a unique role depending on the agonist: Counteracting morphine tolerance, contributing to DAMGO tolerance, and having no effect on fentanyl tolerance. These studies reveal that antinociception and tolerance occur via different mechanisms depending on MOPr agonist.

The role of intracellular signaling pathways on mu-opioid receptor agonist induced antinociception and tolerance development

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