Toxicogenomic analysis of a sustained release local anesthetic delivery system

Abstract

Concerns over neurotoxicity have impeded the development of sustained release formulations providing prolonged duration local anesthesia (PDLA) from a single injection, for which there is an urgent clinical need. Here, we have used toxicogenomics to investigate whether nerve injury occurred during week-long continuous sciatic nerve blockade by microspheres containing bupivacaine, tetrodotoxin, and dexamethasone (TBD). Animals treated with amitriptyline solution (our positive control for local anesthetic-associated nerve injury) developed irreversible nerve blockade, had severely abnormal nerve histology, and the expression of hundreds of genes was altered in the dorsal root ganglia at 4 and 7 days after injection. In marked contrast, TBD-treated nerves reverted to normal function, were normal histologically and there were changes in the expression of a small number of genes. Toxicogenomic studies have great potential in delineating patterns of gene expression associated with specific patterns of tissue injury (e.g. amitriptyline neurotoxicity), and in identifying related changes in gene expression upon exposure to a drug, biomaterial, or drug delivery system.