Rapid optical control of nociception with an ion-channel photoswitch

Abstract

Local anesthetics are effective in suppressing pain sensation, but most of these compounds act non-selectively, inhibiting the activity of all neurons. Moreover, their actions abate slowly, preventing precise spatial and temporal control of nociception. We have developed a photoisomerizable molecule named QAQ (Quaternary ammonium – Azobenzene – Quaternary ammonium) that enables rapid and selective optical control of nociception. QAQ is membrane-impermeant and it has no effect on most cells, but it infiltrates pain-sensing neurons through endogenous ion channels that are activated by noxious stimuli, primarily TRPV1. After QAQ accumulates intracellularly, it blocks voltage-gated ion channels in the trans but not the cis form. QAQ enables reversible optical silencing of mouse nociceptive neuron firing without exogenous gene expression and can serve as a light-sensitive analgesic in rats in vivo. Moreover, because intracellular QAQ accumulation is a consequence of nociceptive ion channel activity, QAQ-mediated photosensitization provides a new platform for understanding signaling mechanisms in acute and chronic pain.

Permeation and block of TRPV1 channels by the cationic lidocaine derivative QX-314

“…These experiments were motivated by the concept of using TRPV1 channels as portals for delivering charged drug molecules into primary pain-sensing neurons to inhibit pain signaling in vivo selectively Kim et al 2010;Liu et al 2011;Roberson et al 2011), an approach recently extended to using light-controlled QX-314 derivatives (Mourot et al 2012) and to using TRPA1 channels as portals (Lennertz et al 2012). Our finding that QX-314 can enter through the standard pore and does not require pore dilation is likely advantageous for in vivo and potential clinical use because pore dilation typically requires large concentrations of agonist (Banke et al 2010;Chung et al 2008), which may be difficult to deliver and maintain in vivo (e.g., using perineural infusion to produce nerve block).…”

Shedding Light On Photo-Switchable Analgesics For Pain

“…Quaternary ammonium-azobenzene-quaternary ammonium (QAQ) is a photo-switchable compound developed on the basis of lidocaine and its derivative QX-314, local anesthetics that block voltage-gated channels [7,8]. Trans-QAQ is capable of blocking ion channels, but the cis form is inactive.…”

“…Under prolonged pain conditions, QAQ inhibitory effect does not seem to need a co-targeting of TRPV1, due to the fact that active nociceptive neurons would allow its internalization [7,8]. An in vivo test was also performed by topical application of QAQ to rats' cornea, where von Frey hair evoked responses demonstrated that trans-QAQ could block blink sensitivity f ollowing irradiation of 380 nm light [8].…”

Photochromic Materials in Biochemistry

“…This approach involves genetic manipulation of the protein so that a reactive cysteine residue can be placed in a specific site on the receptor. A second method involves a small molecule ligand that contains a head group that resembles a known receptor agonist or antagonist [74,[79][80][81][82][83][84][85]. The affinity is light dependent, the conformation of one isomer interferes with binding and/or activation and the other permits it.…”