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Morphine tolerance does not develop in mice treated with endothelin-A receptor antagonists.
Shaifali Bhalla1, George Matwyshyn, Anil Gulati
1Department of Biopharmaceutical Sciences (M/C 865), University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
Brain Research
|November 18, 2005
Summary
Endothelin (ET) receptor antagonists, BQ123 and BMS182874, enhance morphine
Area of Science:
- Pharmacology
- Neuroscience
- Pain Research
Background:
- Long-term morphine use induces antinociceptive tolerance.
- Central endothelin (ET) mechanisms are implicated in morphine tolerance development.
Purpose of the Study:
- Investigate the effect of ET(A) receptor antagonists (BQ123, BMS182874) on morphine antinociception and tolerance.
- Elucidate the interaction mechanism between ET(A) receptor antagonists and morphine.
Main Methods:
- Administered ET(A) receptor antagonists (BQ123, BMS182874) intracerebroventricularly in mice.
- Assessed morphine antinociception and tolerance.
- Performed naloxone binding assays.
- Measured [35S]GTPgammaS binding to assess G protein activation.
Main Results:
- BQ123 and BMS182874 significantly enhanced morphine's antinociceptive effect.
- A single dose of BQ123 reversed established morphine tolerance.
- Antagonists did not bind to opioid receptors, as shown by unchanged naloxone binding.
- Morphine and ET-1 induced G protein activation was reduced in tolerant mice.
- BQ123 and BMS182874 restored G protein activation in tolerant mice.
Conclusions:
- ET(A) receptor antagonists potentiate morphine antinociception.
- These antagonists reverse morphine tolerance by promoting G protein coupling to opioid receptors.
- This mechanism highlights a novel therapeutic strategy for managing opioid tolerance.