Coapplication of Lidocaine and the Permanently Charged Sodium Channel Blocker QX-314 Produces a Long-lasting Nociceptive Blockade in Rodents

Abstract

Background Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314–mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia. Methods Lidocaine (0.5% [17.5 mm], 1% [35 mm], and 2% [70 mm]) alone, QX-314 (0.2% [5.8 mm]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block. Results Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block. Conclusions Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…However, when coadministered with capsaicin, QX-314 enters the sensory neuron through the open TRPV1 pore and gains access to its binding site on the sodium channel (Binshtok et al, 2007). This elegant approach affords selective targeting of TRPV1-expressing sensory neurons (Binshtok et al, 2007(Binshtok et al, , 2009). This approach was recently further refined by identifying such TRPV1 agonists (e.g., Cap-ET) that recognize and selectively target already sensitized TRPV1 channels in inflamed tissues and augment the uptake of QX-314 (Li et al, 2011a).…”

Etiology and Pharmacology of Neuropathic Pain

“…Another emerging approach to pain management is to introduce drugs into the neuronal cytoplasm via the open pore of TRP channels (Binshtok et al, 2007(Binshtok et al, , 2009). This may be achieved by direct activation of TRPV1 by capsaicin or indirect activation of other drug-permeable channels via Toll-like receptor 5 (TLR5) (Peirs and Seal, 2015;Xu et al, 2015).…”

Pengujian Efektivitas Capsicum Sebagai Sumber Capsaicin Ko-Anestesi Pada Anestesi Lokal

“…Untuk mengatasi permasalahan ini maka dikembangkan suatu prinsip anestesi lokal baru dimana anestesi lokal yang digunakan memblok sel saraf sensorik yang hanya mengantarkan impuls rasa sakit, yakni dengan cara memberi zat-zat tambahan (ko-anestesi) agar dapat bekerja secara 4 . Salah satu zat ko-anestesi tersebut adalah capsaicin yang terdapat pada cabai (Capsicum) 5 . Nosiseptor ini terdapat saluran Transient Receptor Potential Vanilloid 1 (TRPV1) sebagai transduser termosensitif yang dapat diaktivasi oleh sifat panas (iritan) pada capsaicin, sedangkan pada sel saraf lain saluran TRPV1 ini tidak diekspresikan 6 .…”

“…Dengan kadar Dyhidrocapsaicin ini perbedaan hasil yang konsisten pada kelompok cabai konsentrasi 5% dengan 10% pada jenis cabai yang sama dapat dijelaskan. Kelompok cabai konsentrasi 5% memiliki waktu aktif efek motorik yang lebih cepat dikarenakan kadar dihydrocapsaicin yang dimiliki lebih kecil dibandingkan dengan kelompok cabai sejenis pada konsentrasi 10%, terkecuali untuk kelompok cabai hijau yang tidak memiliki kandungan Dihydrocapsaicin 5 .…”

“…Dimana cabai dari kelompok ini memiliki kadar Capsaicin terlarut yang terendah dibandingkan kelompok cabai merah keriting dan cabai rawit. Sedangkan bila dibandingkan dengan kelompok cabai hijau yang memiliki waktu blokade sensorik yang lebih lama, hal ini diakibatkan hampir sepertiga komponen zat aktif kelompok cabai merah adalah Dihydrocapsaicin, sedangkan tidak ada sama sekali pada kelompok cabai hijau 5 .…”