Abstract
BackgroundMorphine tolerance is a common drawback of chronic morphine exposure, hindering use of this drug. Studies have shown that PKCã may play a key role in the development of morphine tolerance, although the mechanisms are not fully known.Methodology/Principal FindingsIn a rat model of morphine tolerance, PKCã knockdown in the spinal cord was successfully carried out using RNA interference (RNAi) with lentiviral vector-mediated short hairpin RNA of PKCã (LV-shPKCã). Spinal cords (L4-L5) were obtained surgically from morphine-tolerant (MT) rats with and without PKCã knockdown, for comparative proteomic analysis. Total proteins from the spinal cords (L4-L5) were extracted and separated using two-dimensional gel electrophoresis (2DGE); 2D gel images were analyzed with PDQuest software. Seven differential gel-spots were observed with increased spot volume, and 18 spots observed with decreased spot volume. Among these, 13 differentially expressed proteins (DEPs) were identified with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), comparing between MT rats with and without PKCã knockdown. The DEPs identified have roles in the cytoskeleton, as neurotrophic factors, in oxidative stress, in ion metabolism, in cell signaling, and as chaperones. Three DEPs (GFAP, FSCN and GDNF) were validated with Western blot analysis, confirming the DEP data. Furthermore, using immunohistochemical analysis, we reveal for the first time that FSCN is involved in the development of morphine tolerance.Conclusions/SignificanceThese data cast light on the proteins associated with the PKCã activity during morphine tolerance, and hence may contribute to clarification of the mechanisms by which PKCã influences MT.
Highlights
Morphine is the cornerstone of the management of both cancer pain and postoperative pain
During the development of morphine tolerance, there were no differences in the paw withdrawal latencies (PWLs) between LV-NC and LV-shPKCarats
Maximal reversal of anti-nociceptive tolerance to morphine was observed 7 days after siRNA injection; we examined the effect of LV-shPKCainjection on protein expression at day 14
Summary
Morphine is the cornerstone of the management of both cancer pain and postoperative pain. Treatment with morphine is often accompanied by the development of tolerance and dependence [1]. It is well established that morphine exerts its antinociceptive effect mainly through activation of the mu opioid receptor (MOR), but that morphine tolerance and physical dependence do not require modification of the MOR [2,3]. Studies have shown that morphine tolerance is related to adaptation of numerous process in the central nervous system, such as N-methyl-d-aspartate receptors, and neuropeptide and opioid systems, but the mechanisms underlying this phenomenon are still not clearly understood [4,5,6]. Studies have shown that PKCamay play a key role in the development of morphine tolerance, the mechanisms are not fully known
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