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The effect of local anesthetics, particularly those which are hydrophilic, such as tetrodotoxin, is impeded by tissue barriers that restrict access to individual nerve cells. Methods of enhancing penetration of tetrodotoxin into nerve include co-administration with chemical permeation enhancers, nanoencapsulation, and insonation with very low acoustic intensity ultrasound and microbubbles. In this study, we examined the effect of acoustic intensity on nerve block by tetrodotoxin and compared it to the effect on nerve block by bupivacaine, a more hydrophobic local anesthetic. Anesthetics were applied in peripheral nerve blockade in adult Sprague-Dawley rats. Insonation with 1-MHz ultrasound at acoustic intensity greater than 0.5 W/cm 2 improved nerve block effectiveness, increased nerve block reliability, and prolonged both sensory and motor nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. These effects were not enhanced by microbubbles. There was minimal or no tissue injury from ultrasound treatment. Insonation did not enhance nerve block from bupivacaine. Using an in vivo model system of local anesthetic delivery, we studied the effect of acoustic intensity on insonation-mediated drug delivery of local anesthetics to the peripheral nerve. We found that insonation alone (at intensities greater than 0.5 W/cm 2 ) enhanced nerve blockade mediated by the hydrophilic ultra-potent local anesthetic, tetrodotoxin. Graphical abstract.

Local anesthesia enhanced with increasing high-frequency ultrasound intensity