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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Evidence for a role of CaMKIV in the development of opioid analgesic tolerance

Shanelle W Ko1, Yongheng Jia, Hui Xu

  • 1Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, 1 King's College Circle, Medical Sciences Building Rm3342, Toronto, Canada, M5S 1A8.

The European Journal of Neuroscience
|April 25, 2006
PubMed

Insights

Calcium-calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in developing opioid analgesic tolerance. CaMKIV knockout mice showed reduced tolerance to morphine, indicating CaMKIV

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • cAMP response-element binding protein (CREB) is crucial for learning, memory, and addiction.
  • Calcium-calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates CREB.

Purpose of the Study:

  • To investigate the role of CaMKIV in the development of opioid analgesic tolerance and physical dependence.

Main Methods:

  • Utilized CaMKIV-knockout (KO) mice and wild-type (WT) littermates.
  • Administered chronic morphine to assess analgesic tolerance and physical dependence.
  • Measured CREB phosphorylation, micro-opioid receptor expression/phosphorylation, and G-protein uncoupling.
  • Assessed changes in inhibitory transmission.

Main Results:

  • CaMKIV-KO mice exhibited significantly less analgesic tolerance to chronic morphine compared to WT mice.
  • No differences in physical dependence or acute morphine analgesia were observed between groups.
  • Chronic morphine-induced increase in phosphorylated CREB was absent in CaMKIV-KO mice.
  • CaMKIV-KO mice showed reduced G-protein uncoupling from the micro-opioid receptor after morphine treatment.
  • Morphine decreased inhibitory transmission more in CaMKIV-KO mice post-chronic exposure.

Conclusions:

  • CaMKIV is critically involved in the development of opioid analgesic tolerance.
  • CaMKIV does not appear to play a significant role in the development of physical dependence on morphine.
  • These findings highlight CaMKIV as a potential therapeutic target for managing opioid tolerance.

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