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.
Pharmacology, Toxicology and Pharmaceutical Science
1
6%
Agricultural and Biological Sciences
1
6%
Social Sciences
1
6%
Medicine and Dentistry
1
6%
Other
0
0%
Unknown
7
39%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 29 December 2014.
All research outputs
#24,756,754
of 34,364,397 outputs
Outputs from PLOS ONE
#157,368
of 224,528 outputs
Outputs of similar age
#292,534
of 421,360 outputs
Outputs of similar age from PLOS ONE
#2,689
of 4,037 outputs
Altmetric has tracked 34,364,397 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 224,528 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 17.2. This one is in the 21st percentile – i.e., 21% of its peers scored the same or lower than it.
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We're also able to compare this research output to 4,037 others from the same source and published within six weeks on either side of this one. This one is in the 26th percentile – i.e., 26% of its contemporaries scored the same or lower than it.
