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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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GRK/PKC contributes to the expression of fentanyl tolerance, and JNK contributes to the expression of morphine tolerance.A) Microinjection of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) into the ventrolateral PAG 20 min prior to administration of cumulative doses of morphine on Trial 5 enhanced the expression of morphine tolerance (F(1,71)  = 5.061, p = .0276). B) In contrast, microinjection of Ro 32-0432 on Trial 5 reversed the expression of fentanyl tolerance (F(1,76)  = 10.55, p = .0017). C) Microinjection of the JNK inhibitor SP600125 (100 ng/0.4 µL) on Trial 5 reversed the expression of morphine tolerance (F(1,76)  = 4.436, p = .0385), but D) had no effect on the expression of fentanyl tolerance (F(1,81)  = 0.880, p = .351).
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pone-0114269-g005: GRK/PKC contributes to the expression of fentanyl tolerance, and JNK contributes to the expression of morphine tolerance.A) Microinjection of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) into the ventrolateral PAG 20 min prior to administration of cumulative doses of morphine on Trial 5 enhanced the expression of morphine tolerance (F(1,71)  = 5.061, p = .0276). B) In contrast, microinjection of Ro 32-0432 on Trial 5 reversed the expression of fentanyl tolerance (F(1,76)  = 10.55, p = .0017). C) Microinjection of the JNK inhibitor SP600125 (100 ng/0.4 µL) on Trial 5 reversed the expression of morphine tolerance (F(1,76)  = 4.436, p = .0385), but D) had no effect on the expression of fentanyl tolerance (F(1,81)  = 0.880, p = .351).

Mentions: Microinjection of the GRK/PKC inhibitor Ro 32-0432 into the ventrolateral PAG enhanced the expression of morphine tolerance (Fig. 5A), but reversed fentanyl tolerance (Fig. 5B). In contrast, microinjection of the JNK inhibitor SP600125 attenuated the expression of morphine tolerance as indicated by a leftward shift in the morphine dose response curve (Fig. 5C), but had no effect on the fentanyl dose response curve (Fig. 5D). The D50 value for each condition is presented in Table 1. These data demonstrate ligand-biased activation of distinct signaling molecules in the expression of tolerance: GRK/PKC activation contributes to the expression of fentanyl tolerance and JNK activation contributes to the expression of morphine tolerance.


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)

GRK/PKC contributes to the expression of fentanyl tolerance, and JNK contributes to the expression of morphine tolerance.A) Microinjection of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) into the ventrolateral PAG 20 min prior to administration of cumulative doses of morphine on Trial 5 enhanced the expression of morphine tolerance (F(1,71)  = 5.061, p = .0276). B) In contrast, microinjection of Ro 32-0432 on Trial 5 reversed the expression of fentanyl tolerance (F(1,76)  = 10.55, p = .0017). C) Microinjection of the JNK inhibitor SP600125 (100 ng/0.4 µL) on Trial 5 reversed the expression of morphine tolerance (F(1,76)  = 4.436, p = .0385), but D) had no effect on the expression of fentanyl tolerance (F(1,81)  = 0.880, p = .351).
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pone-0114269-g005: GRK/PKC contributes to the expression of fentanyl tolerance, and JNK contributes to the expression of morphine tolerance.A) Microinjection of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) into the ventrolateral PAG 20 min prior to administration of cumulative doses of morphine on Trial 5 enhanced the expression of morphine tolerance (F(1,71)  = 5.061, p = .0276). B) In contrast, microinjection of Ro 32-0432 on Trial 5 reversed the expression of fentanyl tolerance (F(1,76)  = 10.55, p = .0017). C) Microinjection of the JNK inhibitor SP600125 (100 ng/0.4 µL) on Trial 5 reversed the expression of morphine tolerance (F(1,76)  = 4.436, p = .0385), but D) had no effect on the expression of fentanyl tolerance (F(1,81)  = 0.880, p = .351).
Mentions: Microinjection of the GRK/PKC inhibitor Ro 32-0432 into the ventrolateral PAG enhanced the expression of morphine tolerance (Fig. 5A), but reversed fentanyl tolerance (Fig. 5B). In contrast, microinjection of the JNK inhibitor SP600125 attenuated the expression of morphine tolerance as indicated by a leftward shift in the morphine dose response curve (Fig. 5C), but had no effect on the fentanyl dose response curve (Fig. 5D). The D50 value for each condition is presented in Table 1. These data demonstrate ligand-biased activation of distinct signaling molecules in the expression of tolerance: GRK/PKC activation contributes to the expression of fentanyl tolerance and JNK activation contributes to the expression of morphine tolerance.

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