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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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Microinjection of morphine and fentanyl into the ventrolateral PAG produced antinociception on Trial 1.Despite different doses and test times, microinjection of morphine (tested 30 min after a dose of 5 µg, N = 32) or fentanyl (tested 3 min after a dose of 3 µg, N = 33) produced a significant increase in hot plate (HP) latency compared to saline treated controls tested 30 or 3 min after the microinjection (F(3,136) = 51.60; p = .0001).
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pone-0114269-g004: Microinjection of morphine and fentanyl into the ventrolateral PAG produced antinociception on Trial 1.Despite different doses and test times, microinjection of morphine (tested 30 min after a dose of 5 µg, N = 32) or fentanyl (tested 3 min after a dose of 3 µg, N = 33) produced a significant increase in hot plate (HP) latency compared to saline treated controls tested 30 or 3 min after the microinjection (F(3,136) = 51.60; p = .0001).

Mentions: Microinjection of morphine or fentanyl into the ventrolateral PAG on Trial 1 caused a significant increase in hot plate latency compared to saline-pretreated animals as expected (Fig. 4; F(3,136)  = 51.60; p = .0001). The magnitude of antinociception produced by these doses and test times resulted in a slightly greater antinociception for morphine (5 µg/0.4 µL at 30 min) compared to fentanyl (3 µg/0.4 µL at 3 min) treated rats (t(63)  = 2.376, p = .02), but this difference was small compared to the magnitude of antinociception in both groups (Fig. 4). The same doses were injected on Trials 2–4, but nociception was not assessed following these injections to prevent the development of behavioral tolerance from repeated testing [18], [19]. Each of these groups was divided into two conditions on Trial 5 to determine the effects of Ro 32-0432 and SP600125 on the expression of morphine and fentanyl 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)

Microinjection of morphine and fentanyl into the ventrolateral PAG produced antinociception on Trial 1.Despite different doses and test times, microinjection of morphine (tested 30 min after a dose of 5 µg, N = 32) or fentanyl (tested 3 min after a dose of 3 µg, N = 33) produced a significant increase in hot plate (HP) latency compared to saline treated controls tested 30 or 3 min after the microinjection (F(3,136) = 51.60; p = .0001).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0114269-g004: Microinjection of morphine and fentanyl into the ventrolateral PAG produced antinociception on Trial 1.Despite different doses and test times, microinjection of morphine (tested 30 min after a dose of 5 µg, N = 32) or fentanyl (tested 3 min after a dose of 3 µg, N = 33) produced a significant increase in hot plate (HP) latency compared to saline treated controls tested 30 or 3 min after the microinjection (F(3,136) = 51.60; p = .0001).
Mentions: Microinjection of morphine or fentanyl into the ventrolateral PAG on Trial 1 caused a significant increase in hot plate latency compared to saline-pretreated animals as expected (Fig. 4; F(3,136)  = 51.60; p = .0001). The magnitude of antinociception produced by these doses and test times resulted in a slightly greater antinociception for morphine (5 µg/0.4 µL at 30 min) compared to fentanyl (3 µg/0.4 µL at 3 min) treated rats (t(63)  = 2.376, p = .02), but this difference was small compared to the magnitude of antinociception in both groups (Fig. 4). The same doses were injected on Trials 2–4, but nociception was not assessed following these injections to prevent the development of behavioral tolerance from repeated testing [18], [19]. Each of these groups was divided into two conditions on Trial 5 to determine the effects of Ro 32-0432 and SP600125 on the expression of morphine and fentanyl 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