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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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Analysis of GRK/PKC and JNK inhibition on morphine and fentanyl antinociception.Rats were injected with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl), the JNK inhibitor SP600125 (100 ng/0.4 µL), or the appropriate vehicle into the ventrolateral PAG 20 min before microinjection of cumulative doses of morphine or fentanyl (N = 7–11/condition). Morphine or fentanyl administration produced a dose dependent increase in hot plate (HP) latency. Microinjection of Ro 32-0432 into the ventrolateral PAG enhanced the antinociceptive effect of morphine (A) as indicated by a leftward shift in the morphine dose-response curve, but had no effect on fentanyl antinociception (B). Neither morphine (C) nor fentanyl (D) antinociception were altered by microinjection of SP600125 into the ventrolateral PAG.
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pone-0114269-g003: Analysis of GRK/PKC and JNK inhibition on morphine and fentanyl antinociception.Rats were injected with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl), the JNK inhibitor SP600125 (100 ng/0.4 µL), or the appropriate vehicle into the ventrolateral PAG 20 min before microinjection of cumulative doses of morphine or fentanyl (N = 7–11/condition). Morphine or fentanyl administration produced a dose dependent increase in hot plate (HP) latency. Microinjection of Ro 32-0432 into the ventrolateral PAG enhanced the antinociceptive effect of morphine (A) as indicated by a leftward shift in the morphine dose-response curve, but had no effect on fentanyl antinociception (B). Neither morphine (C) nor fentanyl (D) antinociception were altered by microinjection of SP600125 into the ventrolateral PAG.

Mentions: Microinjection of Ro 32-0432 into the ventrolateral PAG to block GRK/PKC activation enhanced the antinociceptive effect of morphine, but had no effect on fentanyl antinociception (Figs. 3A & B). A significant leftward shift in the morphine dose response curve was evident in rats treated with Ro 32-0432 compared to vehicle treated controls (F(1,101)  = 11.66, p = .0009). The fentanyl dose-response curves were nearly identical whether rats were treated with Ro 32-0432 or vehicle (F(1,96)  = 0.001, p = .97). The enhancement of morphine antinociception by Ro 32-0432 administration is consistent with prolonged G-protein signaling as a result of blocking MOPr phosphorylation [14].


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)

Analysis of GRK/PKC and JNK inhibition on morphine and fentanyl antinociception.Rats were injected with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl), the JNK inhibitor SP600125 (100 ng/0.4 µL), or the appropriate vehicle into the ventrolateral PAG 20 min before microinjection of cumulative doses of morphine or fentanyl (N = 7–11/condition). Morphine or fentanyl administration produced a dose dependent increase in hot plate (HP) latency. Microinjection of Ro 32-0432 into the ventrolateral PAG enhanced the antinociceptive effect of morphine (A) as indicated by a leftward shift in the morphine dose-response curve, but had no effect on fentanyl antinociception (B). Neither morphine (C) nor fentanyl (D) antinociception were altered by microinjection of SP600125 into the ventrolateral PAG.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0114269-g003: Analysis of GRK/PKC and JNK inhibition on morphine and fentanyl antinociception.Rats were injected with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl), the JNK inhibitor SP600125 (100 ng/0.4 µL), or the appropriate vehicle into the ventrolateral PAG 20 min before microinjection of cumulative doses of morphine or fentanyl (N = 7–11/condition). Morphine or fentanyl administration produced a dose dependent increase in hot plate (HP) latency. Microinjection of Ro 32-0432 into the ventrolateral PAG enhanced the antinociceptive effect of morphine (A) as indicated by a leftward shift in the morphine dose-response curve, but had no effect on fentanyl antinociception (B). Neither morphine (C) nor fentanyl (D) antinociception were altered by microinjection of SP600125 into the ventrolateral PAG.
Mentions: Microinjection of Ro 32-0432 into the ventrolateral PAG to block GRK/PKC activation enhanced the antinociceptive effect of morphine, but had no effect on fentanyl antinociception (Figs. 3A & B). A significant leftward shift in the morphine dose response curve was evident in rats treated with Ro 32-0432 compared to vehicle treated controls (F(1,101)  = 11.66, p = .0009). The fentanyl dose-response curves were nearly identical whether rats were treated with Ro 32-0432 or vehicle (F(1,96)  = 0.001, p = .97). The enhancement of morphine antinociception by Ro 32-0432 administration is consistent with prolonged G-protein signaling as a result of blocking MOPr phosphorylation [14].

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