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Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Abstract:
The aim of this study was to determine whether chronic opioid treatment could influence the protein kinase C (PKC) activity in the rat brain. Chronic morphine (microns agonist) but not butorphanol (mu/delta/kappa mixed agonist) treatment enhanced cytosolic PKC activity in the pons/medulla, but not in the cytosolic fractions of cortex and midbrain regions. Concomitant administration of the opioid receptor antagonist, naloxone, blocked the PKC upregulation by chronic morphine. Chronic administration of morphine and butorphanol produced no change in the membrane PKC activity. Antinociceptive tolerance to morphine but not to butorphanol was developed under these conditions. These results suggest that chronic morphine administration leads to an upregulation of the cytosolic PKC activity in the pons/medulla through repeated activation of mu opioid receptors and that the PKC upregulation in this specific area may contribute to the morphine tolerance.
Insights
Chronic morphine, but not butorphanol, increased protein kinase C (PKC) activity in rat brain regions, suggesting a link between PKC upregulation and morphine tolerance.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic opioid use can lead to tolerance, necessitating a deeper understanding of underlying molecular mechanisms.
- Protein Kinase C (PKC) is implicated in various cellular signaling pathways, including those potentially involved in opioid receptor function.
Purpose of the Study:
- To investigate the effect of chronic opioid treatment on protein kinase C (PKC) activity in specific rat brain regions.
- To determine if changes in PKC activity correlate with the development of antinociceptive tolerance.
Main Methods:
- Rats were administered chronic morphine (mu agonist) or butorphanol (mixed agonist) and their brain tissues (pons/medulla, cortex, midbrain) were analyzed for PKC activity.
- The role of mu opioid receptors was assessed using naloxone, an opioid receptor antagonist.
- Antinociceptive tolerance was evaluated in response to chronic opioid administration.
Main Results:
- Chronic morphine treatment significantly enhanced cytosolic PKC activity in the pons/medulla, but not in the cortex or midbrain.
- Butorphanol did not alter PKC activity in any tested brain region.
- Naloxone administration blocked the PKC upregulation induced by chronic morphine.
- No changes in membrane-bound PKC activity were observed with either opioid.
- Antinociceptive tolerance developed to morphine but not to butorphanol.
Conclusions:
- Chronic morphine administration upregulates cytosolic PKC activity in the pons/medulla via mu opioid receptor activation.
- This PKC upregulation in the pons/medulla may play a significant role in the development of morphine tolerance.
- The findings highlight a specific molecular pathway contributing to opioid tolerance.