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

Morgan MM, Reid RA, Saville KA - PLoS ONE (2014)

Bottom Line: Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Washington State University Vancouver, Vancouver, Washington, 98686, United States of America.

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.

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Model of MOPr signaling showing that distinct molecules contribute to the development and expression of opioid tolerance.Tolerance could be caused by a change anywhere along the signaling pathway. If this change occurs at point C in the model, then repeated co-administration of an opioid with a drug that blocks signaling at points A, B, or C will prevent the development of tolerance. Once tolerance has developed, blocking signaling at points A or B will have no effect on the expression of tolerance because signaling at point C is already altered. However, a drug that blocks the enhanced signaling from points C, D, or E will block the expression of tolerance.
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pone-0114269-g001: Model of MOPr signaling showing that distinct molecules contribute to the development and expression of opioid tolerance.Tolerance could be caused by a change anywhere along the signaling pathway. If this change occurs at point C in the model, then repeated co-administration of an opioid with a drug that blocks signaling at points A, B, or C will prevent the development of tolerance. Once tolerance has developed, blocking signaling at points A or B will have no effect on the expression of tolerance because signaling at point C is already altered. However, a drug that blocks the enhanced signaling from points C, D, or E will block the expression of tolerance.

Mentions: The primary problem is that there are multiple mechanisms for opioid tolerance and the contribution of a specific mechanism varies with subtle differences in experimental design. For example, different mechanisms are engaged in different parts of the nervous system as demonstrated by the involvement of NMDA receptors in tolerance when morphine is administered to the spinal cord, but not to the periaqueductal gray (PAG) [3], [4]. Second, the signaling molecules involved in tolerance may differ depending on whether the development or expression of tolerance is assessed (Fig. 1). Third, different molecules contribute to tolerance to different opioids. Tolerance occurs to morphine, 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].


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

Morgan MM, Reid RA, Saville KA - PLoS ONE (2014)

Model of MOPr signaling showing that distinct molecules contribute to the development and expression of opioid tolerance.Tolerance could be caused by a change anywhere along the signaling pathway. If this change occurs at point C in the model, then repeated co-administration of an opioid with a drug that blocks signaling at points A, B, or C will prevent the development of tolerance. Once tolerance has developed, blocking signaling at points A or B will have no effect on the expression of tolerance because signaling at point C is already altered. However, a drug that blocks the enhanced signaling from points C, D, or E will block the expression of tolerance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263532&req=5

pone-0114269-g001: Model of MOPr signaling showing that distinct molecules contribute to the development and expression of opioid tolerance.Tolerance could be caused by a change anywhere along the signaling pathway. If this change occurs at point C in the model, then repeated co-administration of an opioid with a drug that blocks signaling at points A, B, or C will prevent the development of tolerance. Once tolerance has developed, blocking signaling at points A or B will have no effect on the expression of tolerance because signaling at point C is already altered. However, a drug that blocks the enhanced signaling from points C, D, or E will block the expression of tolerance.
Mentions: The primary problem is that there are multiple mechanisms for opioid tolerance and the contribution of a specific mechanism varies with subtle differences in experimental design. For example, different mechanisms are engaged in different parts of the nervous system as demonstrated by the involvement of NMDA receptors in tolerance when morphine is administered to the spinal cord, but not to the periaqueductal gray (PAG) [3], [4]. Second, the signaling molecules involved in tolerance may differ depending on whether the development or expression of tolerance is assessed (Fig. 1). Third, different molecules contribute to tolerance to different opioids. Tolerance occurs to morphine, 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].

Bottom Line: Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Washington State University Vancouver, Vancouver, Washington, 98686, United States of America.

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.

Show MeSH
Related in: MedlinePlus