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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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Location of representative microinjection sites in the ventrolateral PAG.Morphine injections (filled squares) are shown on the left and fentanyl injections (filled circles) on the right even though all injections were administered on the right side of the PAG. The effect of the opioid was compared between rats receiving repeated opioid (closed symbols) and saline injections (open symbols). All injections were located between coronal sections 0.98 and 1.56 from the interaural line [20].
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pone-0114269-g002: Location of representative microinjection sites in the ventrolateral PAG.Morphine injections (filled squares) are shown on the left and fentanyl injections (filled circles) on the right even though all injections were administered on the right side of the PAG. The effect of the opioid was compared between rats receiving repeated opioid (closed symbols) and saline injections (open symbols). All injections were located between coronal sections 0.98 and 1.56 from the interaural line [20].

Mentions: Immediately following testing, rats were exposed to a lethal dose of Halothane. The brain was removed and placed in formalin (10%) for at least 48 hours. Coronal sections through the caudal PAG (100 µm) were made with a vibratome to determine the location of the injection cannula. Only injection sites located within or immediately adjacent to the ventrolateral PAG [20] were included in data analysis (Fig. 2).


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)

Location of representative microinjection sites in the ventrolateral PAG.Morphine injections (filled squares) are shown on the left and fentanyl injections (filled circles) on the right even though all injections were administered on the right side of the PAG. The effect of the opioid was compared between rats receiving repeated opioid (closed symbols) and saline injections (open symbols). All injections were located between coronal sections 0.98 and 1.56 from the interaural line [20].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0114269-g002: Location of representative microinjection sites in the ventrolateral PAG.Morphine injections (filled squares) are shown on the left and fentanyl injections (filled circles) on the right even though all injections were administered on the right side of the PAG. The effect of the opioid was compared between rats receiving repeated opioid (closed symbols) and saline injections (open symbols). All injections were located between coronal sections 0.98 and 1.56 from the interaural line [20].
Mentions: Immediately following testing, rats were exposed to a lethal dose of Halothane. The brain was removed and placed in formalin (10%) for at least 48 hours. Coronal sections through the caudal PAG (100 µm) were made with a vibratome to determine the location of the injection cannula. Only injection sites located within or immediately adjacent to the ventrolateral PAG [20] were included in data analysis (Fig. 2).

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