Drinking-Related Tetrahydroharmans Counteract the Membrane Effects of Local Anesthetic Lidocaine

There is a general consensus in dentistry that successful local anesthesia is frequently difficult in habitual drinkers and alcoholic patients. Neuro-active tetrahydroharmans increase in human body fluids and tissues by consuming alcoholic beverages. To understand such reduced anesthetic efficacy by the drug interaction hypothesis, we studied the influences of drinking-related tetrahydroharmans on membrane fluidization as one of local anesthetic mechanisms. Liposomal membranes prepared with phosphatidylcholine and cholesterol were treated with lidocaine and different tetrahydroharmans separately and in combination, followed by measuring fluorescence polarization to determine their induced changes in membrane fluidity. In contrast to 0.1–2 mg/mL lidocaine, tetrahydroharmans decreased the fluidity of membrane preparations at ∼25 μg/mL with the potency being 1,2,3,4-tetrahydroharman ≫ 1,2,3,4-tetrahydronorharman. 1,2,3,4-Tetrahydroharman counteracted the membrane-fluidizing effects of 1 mg/mL lidocaine at physiologically relevant 0.25–2.5 ng/mL, whereas neither its 6-hydroxyl nor 7-hydroxyl metabolite did at 25–200 ng/mL. Such counteraction at a membrane lipid level may be responsible for the reduction of local anesthetic efficacy in drinkers because 1,2,3,4-tetrahydroharman increases in vivo by ingesting alcoholic beverages.