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Calcium-acting drugs modulate expression and development of chronic tolerance to nicotine-induced antinociception in

M I Damaj1

  • 1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, 23298-0613, USA. mdamaj@hsc.vcu.edu

The Journal of Pharmacology and Experimental Therapeutics
|August 16, 2005
PubMed

Insights

Nicotine tolerance involves neuronal adaptations. This study shows L-type calcium channels and calmodulin protein kinase II are key players in developing and expressing nicotine tolerance in mice.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Nicotine tolerance is a complex phenomenon involving neuronal adaptations beyond drug-receptor interactions.
  • Calcium-dependent second messengers are implicated in postreceptor events contributing to tolerance.

Purpose of the Study:

  • To investigate the role of L-type calcium channels and calcium-dependent calmodulin protein kinase II in the development and expression of nicotine tolerance.
  • To test the hypothesis that these calcium-dependent mechanisms are critical for nicotine tolerance.

Main Methods:

  • A mouse model of nicotine tolerance was established using chronic nicotine infusion.
  • L-type calcium channel modulators (antagonists and activator) and a calmodulin protein kinase II antagonist (KN-62) were administered.
  • Calcium-dependent calmodulin protein kinase II activity was measured in the spinal cord of tolerant mice.

Main Results:

  • Chronic administration of L-type calcium channel antagonists (nimodipine, verapamil) prevented nicotine tolerance.
  • A calcium channel activator (BAYK8644) enhanced nicotine tolerance.
  • Nicotine tolerance was associated with increased calmodulin protein kinase II activity in the spinal cord.
  • Inhibition of calmodulin protein kinase II reduced the expression of nicotine tolerance.

Conclusions:

  • L-type calcium channels are crucial for the development of nicotine tolerance.
  • Calcium-dependent calmodulin protein kinase II activation is involved in the expression and development of nicotine tolerance.
  • Targeting these calcium-dependent pathways may offer strategies for managing nicotine tolerance.

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