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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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Contribution of GRK/PKC and JNK to the development of morphine and fentanyl tolerance.A) Repeated microinjections of morphine into the ventrolateral PAG caused tolerance as evident by a rightward shift in the morphine dose response curve (F(3,157)  = 3.689, p = .0043). Administration of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) with morphine on Trials 1–4 prevented the development of morphine tolerance (p<.05). B) Repeated microinjections of fentanyl into the ventrolateral PAG also caused tolerance (F(3,142)  = 17.10, p = .0001). Administration of Ro 32-0432 on Trials 1–4 caused a rightward shift in the fentanyl dose-response curve whether rats were made tolerant to fentanyl or not (p<.05). C) Microinjection of the JNK inhibitor SP600125 into the ventrolateral PAG with morphine on Trials 1–4 prevented the development of morphine tolerance (F(3,142)  = 13.82, p = .0001). D) Microinjection of SP600125 (100 ng/0.4 µL) with fentanyl on Trials 1–4 prevented the development of fentanyl tolerance (F(3,137)  = 7.866, p = .0001).
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pone-0114269-g007: Contribution of GRK/PKC and JNK to the development of morphine and fentanyl tolerance.A) Repeated microinjections of morphine into the ventrolateral PAG caused tolerance as evident by a rightward shift in the morphine dose response curve (F(3,157)  = 3.689, p = .0043). Administration of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) with morphine on Trials 1–4 prevented the development of morphine tolerance (p<.05). B) Repeated microinjections of fentanyl into the ventrolateral PAG also caused tolerance (F(3,142)  = 17.10, p = .0001). Administration of Ro 32-0432 on Trials 1–4 caused a rightward shift in the fentanyl dose-response curve whether rats were made tolerant to fentanyl or not (p<.05). C) Microinjection of the JNK inhibitor SP600125 into the ventrolateral PAG with morphine on Trials 1–4 prevented the development of morphine tolerance (F(3,142)  = 13.82, p = .0001). D) Microinjection of SP600125 (100 ng/0.4 µL) with fentanyl on Trials 1–4 prevented the development of fentanyl tolerance (F(3,137)  = 7.866, p = .0001).

Mentions: The effect of prior administration of Ro 32-0432 or SP600125 on the development of tolerance was assessed 18 hours after Trial 4 by microinjecting cumulative doses of morphine or fentanyl into the ventrolateral PAG. Repeated microinjections of either morphine or fentanyl into the ventrolateral PAG caused tolerance as evident by a rightward shift in the dose-response curve compared to rats treated with saline on Trials 1–4 (Fig. 7). Administration of Ro 32-0432 with morphine on Trials 1–4 prevented the development of morphine tolerance assessed on Trial 5 (Fig. 7A). In contrast, repeated microinjections of Ro 32-0432, whether with fentanyl or not, reduced fentanyl potency as evident by rightward shifts in the dose-response curves (Fig. 7B). Changes in potency (D50) as a result of repeated morphine or fentanyl administration with and without Ro 32-0432 are shown in Table 2. In sum, inhibition of GRK/PKC activation attenuated the development of morphine tolerance and inhibited fentanyl antinociception.


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)

Contribution of GRK/PKC and JNK to the development of morphine and fentanyl tolerance.A) Repeated microinjections of morphine into the ventrolateral PAG caused tolerance as evident by a rightward shift in the morphine dose response curve (F(3,157)  = 3.689, p = .0043). Administration of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) with morphine on Trials 1–4 prevented the development of morphine tolerance (p<.05). B) Repeated microinjections of fentanyl into the ventrolateral PAG also caused tolerance (F(3,142)  = 17.10, p = .0001). Administration of Ro 32-0432 on Trials 1–4 caused a rightward shift in the fentanyl dose-response curve whether rats were made tolerant to fentanyl or not (p<.05). C) Microinjection of the JNK inhibitor SP600125 into the ventrolateral PAG with morphine on Trials 1–4 prevented the development of morphine tolerance (F(3,142)  = 13.82, p = .0001). D) Microinjection of SP600125 (100 ng/0.4 µL) with fentanyl on Trials 1–4 prevented the development of fentanyl tolerance (F(3,137)  = 7.866, p = .0001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4263532&req=5

pone-0114269-g007: Contribution of GRK/PKC and JNK to the development of morphine and fentanyl tolerance.A) Repeated microinjections of morphine into the ventrolateral PAG caused tolerance as evident by a rightward shift in the morphine dose response curve (F(3,157)  = 3.689, p = .0043). Administration of the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) with morphine on Trials 1–4 prevented the development of morphine tolerance (p<.05). B) Repeated microinjections of fentanyl into the ventrolateral PAG also caused tolerance (F(3,142)  = 17.10, p = .0001). Administration of Ro 32-0432 on Trials 1–4 caused a rightward shift in the fentanyl dose-response curve whether rats were made tolerant to fentanyl or not (p<.05). C) Microinjection of the JNK inhibitor SP600125 into the ventrolateral PAG with morphine on Trials 1–4 prevented the development of morphine tolerance (F(3,142)  = 13.82, p = .0001). D) Microinjection of SP600125 (100 ng/0.4 µL) with fentanyl on Trials 1–4 prevented the development of fentanyl tolerance (F(3,137)  = 7.866, p = .0001).
Mentions: The effect of prior administration of Ro 32-0432 or SP600125 on the development of tolerance was assessed 18 hours after Trial 4 by microinjecting cumulative doses of morphine or fentanyl into the ventrolateral PAG. Repeated microinjections of either morphine or fentanyl into the ventrolateral PAG caused tolerance as evident by a rightward shift in the dose-response curve compared to rats treated with saline on Trials 1–4 (Fig. 7). Administration of Ro 32-0432 with morphine on Trials 1–4 prevented the development of morphine tolerance assessed on Trial 5 (Fig. 7A). In contrast, repeated microinjections of Ro 32-0432, whether with fentanyl or not, reduced fentanyl potency as evident by rightward shifts in the dose-response curves (Fig. 7B). Changes in potency (D50) as a result of repeated morphine or fentanyl administration with and without Ro 32-0432 are shown in Table 2. In sum, inhibition of GRK/PKC activation attenuated the development of morphine tolerance and inhibited fentanyl antinociception.

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