Perineurally injected nerve-blocking agents have limited capability to cross peripheral nerve barriers (PNBs), requiring high doses to block pain signals on axons. This increases the risk of local tissue toxicity and systemic side effects on the cardiovascular and neurological systems. To address this, we explored carboxyl group modification to enhance the permeability of nerve-blocking agents across the PNBs through carrier-mediated transport facilitated by monocarboxylate transporters (MCTs). The enhanced permeability allows for targeted drug delivery to peripheral nerve axons, resulting in a significant reduction in the necessary drug dosage for a long-lasting nerve block. Specifically, we developed a carboxylated prodrug of capsaicin (COOH-CAP) by conjugating it with a carboxyl group via a degradable ester bond. Calcium flux assays, patch-clamp recordings, and body temperature measurements collectively confirmed that COOH-CAP activates TRPV1, with potency comparable to capsaicin. In rats, a single sciatic nerve injection of 3.28 μmol COOH-CAP produced a nociceptive-selective nerve blockade lasting 260 ± 83.7 h without motor impairment or capsaicin-related side effects, approximately 35 times longer than the same dose of plain capsaicin. Even at a lower dose of 1.64 μmol, COOH-CAP still produced nociceptive-selective nerve blockade for 172.0 ± 41.3 h.

Monocarboxylate transporter 1  /  Local anesthetic  /  Prodrug  /  Capsaicin analogue  /  TRPV1  /  Nerve barrier penetration  /  Sensory nerve blockade  /  Long-lasting local anesthesia