Direct effects of morphine but not of fentanyl-type opioids on human 5-HT3A receptors in outside-out patch-clamp studies
Background The alkaloid morphine is historically the oldest opiate, yet still today it has clinically important uses in analgesic therapies. The main analgesic effect of opioids, including synthetic opioids belonging to the family of 4‐anilidopiperidines, is mediated via activation of opioid recepto...
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| Published in: | European journal of pain Vol. 18; no. 8; pp. 1165 - 1172 |
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| Main Authors: | , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
England
Blackwell Publishing Ltd
01-09-2014
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Background
The alkaloid morphine is historically the oldest opiate, yet still today it has clinically important uses in analgesic therapies. The main analgesic effect of opioids, including synthetic opioids belonging to the family of 4‐anilidopiperidines, is mediated via activation of opioid receptors spread throughout the peripheral and central nervous system. However, morphine acting as a ‘dirty’ drug also exhibits effects on other receptor systems, e.g., the serotonergic system and its 5‐HT3 receptor. Therefore, this study focuses on the interaction of morphine and fentanyl‐type opioids (alfentanil, remifentanil and sufentanil) with 5‐HT3A receptors.
Methods
Excised outside‐out patches from human embryonic kidney‐293 cells, stably transfected with the human 5‐HT3A receptor cDNA, were used to determine the opioid effects using the patch‐clamp technique.
Results
Within clinical concentrations, the effects of morphine are concentration‐dependent. Morphine reduced current amplitudes, as well as activation and decay time constants. These effects were not competitive. Contrary to these results, all fentanyl‐type opioids only exerted effects far above their clinical concentration ranges. These effects were not homogenous but varying.
Conclusions
Morphine is an opioid compound exhibiting special antagonistic interaction with 5‐HT3A receptors. This interaction is not shared by the newer synthetic derivatives of the fentanyl‐type opioids in the clinical relevant concentration range. |
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| Bibliography: | DFG - No. BA 1454 ArticleID:EJP463 istex:4CC08627BDCE3966235B54DFABD60D23FCF26708 ark:/67375/WNG-9MPPCJLF-T Figure S1. Concentration-response curves for activation and decay kinetics of currents through the 5-HT3A receptor in excised patches (evoked by 30 μM 5-HT, solid lines) and for comparison in whole-cells (reference of 3 μM 5-HT, dotted lines, data taken from Wittmann et al., 2006, 2008), respectively. Data determining the concentration-response curves is derived from curve fits of the current responses using single exponential and bi-exponential functions, where applicable. Analogue to the concentration-response curves of peak current flow (see Fig. 2), kinetic concentration-response curves for the fentanyl-type opioids were also compiled only from data of the higher concentration ranges. Significances of distinction were calculated where applicable and are shown as * for p < 0.05 and ns for not significant. Coloured bars symbolize ranges of clinical concentrations (see Fig. 2). (a and b) With rising concentrations, morphine initially lesser attenuated activation kinetics in excised patches compared with whole-cell results, but application of 3 μM morphine to excised patches elicited a very strong delay of the activation time constant to 1861.3 ± 1073.4% of controls. Morphine induced a deceleration of decay kinetics within the range as seen on whole-cells. (c and d) Alfentanil, when applied in rising concentrations, accelerated the activation kinetics. When compared with the results from whole-cell experiments, a small difference in acceleration of activation kinetics was seen, but this difference was not significant. An acceleration was also seen for the decay kinetics, in whole-cell, as well as in excised patches. In the latter, the acceleration, progressing with rising alfentanil concentrations, was significantly lesser in excised patches. (e and f) Contrary to data from whole-cell, the activation kinetics in excised patches were decelerated by remifentanil, whereas current decay was not affected. (g and h) In excised patches, sufentanil exerted a slight acceleration in activation kinetics with rising concentrations, the decay kinetics were accelerated in the same fashion. Compared with whole-cell data, the effect of sufentanil on the activation kinetics was just opposite, and the effect on acceleration of current decay was significantly stronger in whole-cells. Funding sources Conflict of interests Supported by the DFG (BA 1454). None declared. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 1090-3801 1532-2149 |
| DOI: | 10.1002/j.1532-2149.2014.00463.x |