Analgesic Agents Share the Membrane Interactivity Possibly Associated with the Diversity of Their Pharmacological Properties

Aim: Various drugs used for pain relief show the diversity of pharmacological properties besides their intrinsic analgesic activity. In order to verify a common mechanism, we studied the effects of selected analgesic agents on lipid bilayer membranes by paying attention to their induced physicochemical membrane modification and stereostructure specificity.
Methodology: Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicle suspensions. The membrane preparations were treated with local anesthetics (lidocaine, bupivacaine and ropivacaine), phenolic sedatives/anesthetics (thymol, eugenol, guaiacol and propofol), non-steroidal anti-inflammatory drugs (ibuprofen and indomethacin), N-methyl-D-aspartate receptor antagonist (ketamine), and their stereoisomers at clinically-relevant concentrations, followed by measuring fluorescence polarization to determine the changes in membrane fluidity.
Results: All the tested drugs interacted with lipid bilayer membranes to modify their fluidity. Lidocaine, bupivacaine, ropivacaine, thymol, eugenol, guaiacol, propofol and ketamine increased the fluidity of neuronal mimetic membranes at 0.1-200 μM, whereas ibuprofen and indomethacin decreased the membrane fluidity at 100-200 μM. In neuronal and myocardial mimetic membranes consisting of 35-40 mol% chiral cholesterol, stereoisomers (25-200 μM) showed the enantiomer-specific membrane effects with the relative potencies being R(+)-bupivacaine > racemic bupivacaine > S(–)-bupivacaine, S(+)-ketamine > racemic ketamine, and S(+)-ibuprofen > racemic ibuprofen > R(–)-ibuprofen, which were correlated with those of their analgesic, anesthetic or cardiotoxic effects.
Conclusion: Analgesic agents share the ability to interact with lipid bilayers, directly influencing the properties and functions of biomembranes at a lipid level and indirectly modulating the activities of membrane-associated ion channels, receptors and enzymes through the conformational changes of proteins. The membrane interactivity possibly accounts for their pharmacological diversity.