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Sign-reversal during persistent activation in mu-opioid signal transduction
L A Bruins Slot1, P J Pauwels, F C Colpaert
1Centre de Recherche Pierre Fabre-17, Avenue Jean Moulin, Castres Cedex, F81106, France. liesbeth.bruins.slot@pierre-fabre.com
Journal of Theoretical Biology
|June 8, 2002
Summary
Opioid receptor activation can cause effects to reverse, even when the input remains constant. This study demonstrates how signal transduction mechanisms lead to sign reversal during continuous opioid signaling.
Area of Science:
- Pharmacology
- Neuroscience
- Cellular Biology
Background:
- Signal transduction interprets inputs based on deviations from past activity.
- Opioid receptor activation typically causes analgesia, but can paradoxically lead to hyperalgesia upon discontinuation.
Purpose of the Study:
- To investigate the phenomenon of effect sign reversal in opioid signaling under sustained activation.
- To explore the underlying transduction mechanisms responsible for these dynamic changes.
Main Methods:
- Numerical simulations based on signal transduction principles.
- In vitro experiments measuring Ca(2+) responses in CHO-K1 cells with mu-opioid receptors.
- In vivo studies involving continuous fentanyl infusion in rats to assess pain responses.
Main Results:
- Morphine initially increased, then decreased intracellular Ca(2+) concentration in vitro.
- Continuous fentanyl infusion in vivo initially produced analgesia, followed by hyperalgesia.
- Simulations predicted and experiments confirmed effect sign reversal under constant input magnitude.
Conclusions:
- Opioid signaling systems possess transduction mechanisms that can reverse the sign of the effect.
- This reversal occurs not only upon cessation of activation but also during sustained, constant-magnitude input.
- Understanding these dynamic signaling properties is crucial for opioid-based therapies.