Functionally selective signaling for morphine and fentanyl antinociception and tolerance mediated by the rat periaqueductal gray.

Michael M Morgan,Kimber A Saville,Rachel A Reid,Allan Siegel

doi:10.1371/journal.pone.0114269

Michael M Morgan, Kimber A Saville + Show 2 more

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https://doi.org/10.1371/journal.pone.0114269

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Journal: PloS one	Publication Date: Dec 11, 2014
Citations: 17	License type: CC BY 4.0

Affiliation: Washington State University Vancouver

Abstract

Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance.

Highlights

Opioids such as morphine and fentanyl are the most commonly used and effective drugs to treat severe pain
Mean hot plate latency went from 13.15¡1.1 to 12.4¡1.6 s following microinjection of SP600125 into the ventrolateral periaqueductal gray (PAG) and from 12.8¡1.0 to 13.8¡1.3 s following microinjection of the SP600125 vehicle. These data indicate that subsequent changes in morphine or fentanyl antinociception caused by blocking G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) or Jun N-terminal kinase (JNK) are not caused by a shift in baseline nociception
Microinjection of Ro 32-0432 into the ventrolateral PAG to block GRK/PKC phosphorylation of the mu-opioid receptor (MOPr) had no effect on baseline nociception, enhanced morphine antinociception, and reversed the expression of fentanyl tolerance

Summary

Introduction

Opioids such as morphine and fentanyl are the most commonly used and effective drugs to treat severe pain. Tolerance to morphine is easy to induce in laboratory animals, and thousands of studies examining the neural mechanisms underlying tolerance have been undertaken. Despite this effort, there is no coherent understanding of the molecular changes that cause opioid tolerance. The signaling molecules involved in tolerance may differ depending on whether the development or expression of tolerance is assessed (Fig. 1). But not fentanyl in G protein-coupled receptor kinase (GRK) knock out mice, whereas blocking C-Jun N-terminal kinase (JNK) disrupts tolerance to a single injection of morphine, but not fentanyl [5]. Others have shown that pharmacological disruption of GRK signaling prevents the expression of tolerance to DAMGO, but not morphine or fentanyl [6]

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