Role of protein kinase C and μ‐opioid receptor (MOPr) desensitization in tolerance to morphine in rat locus coeruleus neurons

Bailey, Christopher; Llorente, Javier; Gabra, Bichoy H.; Smith, Forrest L.; Dewey, William L.; Kelly, Eamonn; Henderson, Graeme

doi:10.1111/j.1460-9568.2008.06573.x

Cited by 89 publications

(125 citation statements)

References 49 publications

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“…A recent study by Bailey et al showed that μ-opioid receptor desensitization was observed in single rat brainstem locus coeruleus neurons following exposure to morphine in vitro and in vivo (16). Interestingly, their study found that μ-opioid receptor desensitization has a significant PKC-dependent component and that this desensitization underlies the maintenance of morphine tolerance (16).…”

Section: Effects Of the Pkc Inhibitor On The Development Of Morphine mentioning

confidence: 99%

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Jin

2009

ACS Chem. Neurosci.

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The present study was performed to investigate the possible role of protein kinase C (PKC) in morphine tolerance at spinal levels of rats. Intrathecal injection of 10 μg of morphine induced increases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in rats. After intrathecal injections of 10 μg of morphine (twice a day) lasted for 5 days, the antinociceptive effects induced by intrathecal injections of morphine decreased significantly in rats. Interestingly, we found that there were significant increases in the content of PKC in the dorsal horn of the spinal cord and the dorsal root ganglion, but not in the ventral horn of the spinal cord, in rats with morphine tolerance determined by Western blot, suggesting that PKC is involved in morphine tolerance at spinal levels of rats. Furthermore, our results demonstrated that chronic intrathecal injection of the PKC inhibitor significantly inhibited the development of morphine tolerance. Moreover, we found that the maintenance of morphine tolerance was blocked by intrathecal administration of a PKC inhibitor in rats, and the inhibitory effects of the PKC inhibitor on morphine tolerance lasted for more than two days. Taken together, the present study clearly showed that PKC is involved in morphine tolerance at the spinal level of rats and that intrathecal administration of a PKC inhibitor can block the development and maintenance of morphine tolerance.Keywords: Development of morphine tolerance, dorsal root ganglion, hindpaw withdrawal latency, maintenance of morphine tolerance, PKC, spinal cord M orphine still proves to be clinically indispensible in treating moderate to severe pain. However, the development of tolerance, antinociceptive effect produced by a given dose of morphine declined over time (1-3), largely limits its extensive application. Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinases, has been demonstrated to play an important role in cellular signal transduction. PKC can be activated upon external stimulation of cells by various ligands including growth factors, hormones, and neurotransmitters (4-6).With the method of [ The results indicate a strong correlation between PKC and morphine tolerance, which was later confirmed by a wide range of other studies (8-11). The present study was performed to explore the role of PKC in morphine tolerance at the spinal level of rats, especial in the development and maintenance of morphine tolerance. Results and DiscussionInfluence of Morphine Tolerance on the Expression of PKC at the Spinal Level of RatsTo investigate the role of PKC in morphine tolerance at the spinal level, rats received intrathecal administration of 10 μg of morphine twice a day for 5 days to produce morphine tolerance. Another group of rats without any treatment was as the control group (n=8).As shown in Figure 1, there were significant increases in the content of PKC (n=5; F=6.34; P<0.05) in the dorsal horn of the spinal cord in rats with morphine tolerance compared wit...

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Section: Effects Of the Pkc Inhibitor On The Development Of Morphine mentioning

confidence: 99%

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Jin

2009

ACS Chem. Neurosci.

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“…Agonist concentrationresponse data from LC neurons were fitted to sigmoidal curves with variable slopes, with the bottom of the curve in each case being constrained to 0, for determination of agonist EC 50 and E max values and for graphical representation of the data. Parameters from this fitting were then used as initial values for fitting of the concentration-response data to the operational model of pharmacological agonism (Black and Leff, 1983;Bailey et al, 2009;McPherson et al, 2010)…”

Section: Drugs Morphine Hydrochloride Was Obtained From Mcfarlanmentioning

confidence: 99%

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

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Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the -opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [DAla 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K ϩ current in a concentrationdependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K ϩ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.

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“…However, morphine induces receptor phosphorylation inefficiently and activates protein kinase C (PKC) via the G protein-dependent pathway (Bohn et al, 2002;Zheng et al, 2008a,b). The participation of activated PKC in receptor signal desensitization and tolerance development has been extensively reported (Bohn et al, 2002;Smith et al, 2002;Zheng et al, 2008b;Bailey et al, 2009;Chu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

FK506-Binding Protein 12 Modulatesμ-Opioid Receptor Phosphorylation and Protein Kinase Cε–Dependent Signaling by Its Direct Interaction with the Receptor

et al. 2013

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Protein kinase C (PKC) activation plays an important role in morphine-induced m-opioid receptor (OPRM1) desensitization and tolerance development. It was recently shown that receptor phosphorylation by G protein-coupled receptor kinase regulates agonist-dependent selective signaling and that inefficient phosphorylation of OPRM1 leads to PKC« activation and subsequent responses. Here, we demonstrate that such receptor phosphorylation and PKC« activation can be modulated by FK506-binding protein 12 (FKBP12). Using a yeast two-hybrid screen, FKBP12 was identified as specifically interacting with OPRM1 at the Pro 353 residue. In human embryonic kidney 293 cells expressing OPRM1, the association of FKBP12 with OPRM1 decreased the agonist-induced receptor phosphorylation at Ser 375. The morphine-induced PKC« activation and the recruitment of PKC« to the OPRM1 signaling complex were attenuated both by FKBP12 short interfering RNA (siRNA) treatment and in cells expressing OPRM1 with a P353A mutation (OPRM1P353A), which leads to diminished activation of PKCdependent extracellular signal-regulated kinases. Meanwhile, the overexpression of FKBP12 enabled etorphine to activate PKC«. Further analysis of the receptor complex demonstrated that morphine treatment enhanced the association of FKBP12 and calcineurin with the receptor. The blockade of the FKBP12 association with the receptor by the siRNA-mediated knockdown of endogenous FKBP12 or the mutation of Pro 353 to Ala resulted in a reduction in PKC« and calcineurin recruitment to the receptor signaling complex. The receptor-associated calcineurin modulates OPRM1 phosphorylation, as demonstrated by the ability of the calcineurin autoinhibitory peptide to increase the receptor phosphorylation. Thus, the association of FKBP12 with OPRM1 attenuates the phosphorylation of the receptor and triggers the recruitment and activation of PKC«.

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Role of protein kinase C and μ‐opioid receptor (MOPr) desensitization in tolerance to morphine in rat locus coeruleus neurons

Cited by 89 publications

References 49 publications

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Involvement of Protein Kinase C in Morphine Tolerance at Spinal Levels of Rats

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

FK506-Binding Protein 12 Modulatesμ-Opioid Receptor Phosphorylation and Protein Kinase Cε–Dependent Signaling by Its Direct Interaction with the Receptor

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