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Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion
Vinicio Granados-Soto1, Iveta Kalcheva, Xiao-Ying Hua
1Department of Anesthesiology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA.
Pain
|April 27, 2000
Summary
Spinal morphine tolerance involves protein kinase C (PKC) phosphorylation. Inhibiting PKC activity prevents the development of morphine tolerance, suggesting PKC is crucial for this effect.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Spinal morphine tolerance is a significant clinical challenge.
- Protein kinase C (PKC) mediated phosphorylation has been hypothesized as a key mechanism.
- Understanding the molecular basis of tolerance is crucial for developing effective pain management strategies.
Purpose of the Study:
- To investigate the role of spinal protein kinase C (PKC) in the development of morphine tolerance.
- To determine if inhibiting PKC activity can prevent or reverse morphine tolerance.
Main Methods:
- Chronic intrathecal (i.t.) infusion of morphine in rats to induce tolerance.
- Assessment of antinociception using probe doses of morphine.
- Administration of PKC inhibitors (chelerythrine, GF109203X) to block tolerance.
- Measurement of dorsal horn PKC phosphorylating activity and protein expression.
Main Results:
- Chronic morphine infusion led to tolerance, evidenced by reduced antinociception.
- Coinfusion or bolus administration of PKC inhibitors prevented the development of morphine tolerance.
- Morphine infusion increased spinal PKC activity and expression of PKCalpha/gamma.
- PKC inhibitors blocked the increase in PKC activity associated with morphine infusion.
Conclusions:
- Spinal morphine tolerance is dependent on increased local PKC phosphorylating activity.
- Blocking spinal PKC activity effectively prevents the expression of morphine tolerance.
- Targeting PKC represents a potential therapeutic strategy to overcome opioid tolerance.