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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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The antinociceptive effects of microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 were not altered by blocking activation of GRK/PKC or JNK.A) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,32)  = 8.592, p = .0003) whether rats were pretreated with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) or not (Bonferroni, t = 0.689, n.s.). B) Likewise, fentanyl antinociception (F(3,29)  = 7.661, p = .0008) was not altered by pretreatment with Ro 32-0432 (t = 1.882, n.s.). C) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,29)  = 29.67, p = .0001) whether rats were pretreated with SP600125 (100 ng/0.4 µL) or not (t = 1.942, n.s.). D) Likewise, fentanyl antinociception (F(3,28)  = 3.194, p = .041) was not altered by SP600125 pretreatment (t = 0.008, n.s.).
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pone-0114269-g006: The antinociceptive effects of microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 were not altered by blocking activation of GRK/PKC or JNK.A) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,32)  = 8.592, p = .0003) whether rats were pretreated with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) or not (Bonferroni, t = 0.689, n.s.). B) Likewise, fentanyl antinociception (F(3,29)  = 7.661, p = .0008) was not altered by pretreatment with Ro 32-0432 (t = 1.882, n.s.). C) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,29)  = 29.67, p = .0001) whether rats were pretreated with SP600125 (100 ng/0.4 µL) or not (t = 1.942, n.s.). D) Likewise, fentanyl antinociception (F(3,28)  = 3.194, p = .041) was not altered by SP600125 pretreatment (t = 0.008, n.s.).

Mentions: Rats received repeated injections of Ro 32-0432, SP600125, or vehicle along with morphine, fentanyl, or saline into the ventrolateral PAG on Trials 1–4 to determine whether GRK/PKC and JNK contribute to the development of tolerance. The antinociception produced by microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 was evident regardless of pretreatment with Ro 32-0432, SP600125, or vehicle (Fig. 6). In no case did repeated microinjection of Ro 32-0432 or SP600125 alter the antinociception evoked by morphine or fentanyl compared to vehicle treated controls given morphine or fentanyl. Each rat received the same drug combination for Trials 1–4, but no behavioral testing was conducted on Trials 2–4.


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)

The antinociceptive effects of microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 were not altered by blocking activation of GRK/PKC or JNK.A) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,32)  = 8.592, p = .0003) whether rats were pretreated with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) or not (Bonferroni, t = 0.689, n.s.). B) Likewise, fentanyl antinociception (F(3,29)  = 7.661, p = .0008) was not altered by pretreatment with Ro 32-0432 (t = 1.882, n.s.). C) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,29)  = 29.67, p = .0001) whether rats were pretreated with SP600125 (100 ng/0.4 µL) or not (t = 1.942, n.s.). D) Likewise, fentanyl antinociception (F(3,28)  = 3.194, p = .041) was not altered by SP600125 pretreatment (t = 0.008, n.s.).
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pone-0114269-g006: The antinociceptive effects of microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 were not altered by blocking activation of GRK/PKC or JNK.A) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,32)  = 8.592, p = .0003) whether rats were pretreated with the GRK/PKC inhibitor Ro 32-0432 (400 ng/0.4 µl) or not (Bonferroni, t = 0.689, n.s.). B) Likewise, fentanyl antinociception (F(3,29)  = 7.661, p = .0008) was not altered by pretreatment with Ro 32-0432 (t = 1.882, n.s.). C) Microinjection of morphine produced an increase in hot plate latency compared to vehicle treated controls (F(3,29)  = 29.67, p = .0001) whether rats were pretreated with SP600125 (100 ng/0.4 µL) or not (t = 1.942, n.s.). D) Likewise, fentanyl antinociception (F(3,28)  = 3.194, p = .041) was not altered by SP600125 pretreatment (t = 0.008, n.s.).
Mentions: Rats received repeated injections of Ro 32-0432, SP600125, or vehicle along with morphine, fentanyl, or saline into the ventrolateral PAG on Trials 1–4 to determine whether GRK/PKC and JNK contribute to the development of tolerance. The antinociception produced by microinjecting morphine or fentanyl into the ventrolateral PAG on Trial 1 was evident regardless of pretreatment with Ro 32-0432, SP600125, or vehicle (Fig. 6). In no case did repeated microinjection of Ro 32-0432 or SP600125 alter the antinociception evoked by morphine or fentanyl compared to vehicle treated controls given morphine or fentanyl. Each rat received the same drug combination for Trials 1–4, but no behavioral testing was conducted on Trials 2–4.

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