Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 sodium channel blockers

Background Capsaicin, the pungent ingredient in chili peppers, is a vanillo id with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primaril y in small-diameter nociceptor afferents of the peripheral nerves, their in hibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. Methods: Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 mu M tetrodotoxin, or both were administered to male Sprague-Dawle y rats. Thermal nociceptive and motor blockade were measured. Data were exp ressed as medians with 25th and 75th percentiles. Results: Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsai cin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that r ats achieved maximal block shown by isobolographic analysis. The combinatio n of tetrodotoxin and capsaicin showed less motor predominance than tetrodo toxin did alone. Similar interactions were found between tetrodotoxin and r esiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (an other site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. Conclusions: Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions maybe useful in deve loping prolonged local anesthetics and elucidating mechanisms of functional ly selective nerve blockade.