Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice

Abstract

Primary nociceptors are the first neurons involved in the complex processing system that regulates normal and pathological pain1. Our ability to excite and inhibit these neurons has been limited by pharmacological and electrical stimulation constraints; non-invasive excitation and inhibition of these neurons in freely moving non-transgenic animals has not been possible. Here we use an optogenetic2 strategy to bidirectionally control nociceptors of non-transgenic mice. Intra-sciatic nerve injection of adeno-associated viruses encoding an excitatory opsin enabled light-inducible stimulation of acute pain, place aversion, and optogenetically mediated reductions in withdrawal thresholds to mechanical and thermal stimuli. In contrast, viral delivery of an inhibitory opsin enabled light-inducible inhibition of acute pain perception, and reversed mechanical allodynia and thermal hyperalgesia in a model of neuropathic pain. Light was delivered transdermally enabling these behaviors to be induced in freely moving animals. This approach may have utility in basic and translational pain research, and enable rapid drug screening and testing of newly engineered opsins.

A novel analgesic approach to optogenetically and specifically inhibit pain transmission using TRPV1 promoter

“…3F), but not with NF200 (Fig. 3E), which is a marker of large-diameter myelinated mechanoreceptors mainly conducting non-noxious stimuli (Iyer et al, 2014). These results confirmed that ArchT is selectively expressed in nociceptors following direct injection of viral vectors into the mice DRG.…”

Optoactivation of parvalbumin neurons in the spinal dorsal horn evokes GABA release that is regulated by presynaptic GABAB receptors

“…In particular, it was difficult to selectively activate a specific type of heterogeneous population of neurons. The incorporation of optogenetics has provided a better understanding of the complex circuit, showing a robust application in pain research from behavioral [4,11] to cellular levels [3,4,21]. In our present study, by selectively expressing ChR2 on PV neurons, we achieved a realtime gain-of-function for specific neuron types and manipulated GABA release by a light pulse.…”

Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

“…The key feature of these devices is that they support multichannel operation, thereby overcoming a critical limitation of the single-channel, single-wavelength capabilities of previously reported wired and wireless systems (7)(8)(9)(10)(11)13). Here, an advanced, stretchable antenna structure integrates multiple capacitive coupling traces to yield nonoverlapping resonances for frequency-selective harvesting and control.…”

“…Although this approach permits simple behavior modeling, constraints in animal motion and alterations in natural behaviors due to fiber tethering and external fixation complicate use in chronic longitudinal models and in experiments that assess complex responses. Many of these limitations can be bypassed with optoelectronic technologies and wireless receivers, as recently demonstrated in optogenetic stimulation of the brain, the peripheral nerves, and the spinal cord (4,(7)(8)(9)(10)(11)(12)(13). Systems that offer soft, compliant mechanical properties and thin, fully implantable designs are particularly advantageous (7).…”