QX-314 Induces Analgesia to Nociceptive Thermal Stimulus by Co-Application with Capsiate or Anandamide

Recently, N-ethyl-lidocaine (QX-314) was demonstrated to pass through a nociceptor membrane when the drug was co-applied with capsaicin, thereby leading to analgesia due to selective blockade of a sodium channel associated with the excitability in nociceptors. However, capsaicin induces a pain in the case of injection with QX-314. Therefore this good idea is unfavorable for a clinical therapy. Then, we exam?ined whether non pungent Capsiate (CST) and arachidonylethanolamide (anandamide: AEA) can deliver QX-314 into nociceptive neurons through the pores of Transient Receptor Protein Vanilloid 1 (TRPV1) and contribute to the antinociceptive effect. Dimethyl sulfoxide (DMSO), CST, QX-314, a mixture (combination) of CST and QX-314 (CST/ QX-314), and a combination of AEA and QX-314 (AEA/QX-314) were injected into the hind paws of rats to evaluate anti-noxious heat effect. A long-lasting sensory nerve block (analgesia) was induced by CST/QX-314 or AEA/QX-314. Especially, the CST/QX-314 caused more effective than our previous studies with the combination of capsaicin and QX-314 (CAP/QX-314). The present results also indicate that CST can induce analgesia by itself. The study aimed at developing a new method with substances distinct from capsai?cin to eliminate the action-potential firing in nociceptors (but effective only for pain sensation). As a result, CST is likely to be a potent candidate for pain relief.