Using lights to turn on/off pain in nontransgenic mice.
(by Haohao Wu, )

Imagine this, one day in the near future, if you suffered from a pain, you need only a hand-held flashlight device to immediately relieve the paininstead of taking pills which may cause side effects or addictive problems. This is not in fantasy films but a new methodology developed recently by Scott Delp and colleagues from Stanford University. This approach takes advantage of optogenetics, using lights to control primary nociceptors which are the first neurons involved in the pain processing system. It is not the first time to optogenetically control pain, two previous studies developed transgenic mouse lines which express light-sensitive protein opsins in defined neuron types to regulate pain. However, requirement of transgenesis limits the application of this approach across species and we are certainly not transgenic humans at this moment. Instead of transgenic technology, Scott Delp and colleagues used virus to introduce opsins into nociceptors in nontransgenic mice, making it possible for applying this method to the therapeutic use in human one day.

In this study, researchers use a kind of virus to deliver the gene of light-activated opsins in nociceptors to excite them (blue light-activated cation channel channelrhodopsin-2, ChR2) or inhibit them (yellow light-sensitive chloride pump halorhodopsin, eNpHR3.0). This was done by a simple injection into the sciatic nerves of mice, and opsins were shown to be expressed with high specificity in nociceptors, especially in regions of the paw innervated by the sciatic nerves. Researchers then used transdermal illumination on the tiny paws of these mice to optogenetically control the nociceptors.

Intrasciatic injection of virus encoding excitatory opsin

Fig. 1: (a)Intrasciatic injection of virus encoding excitatory opsin (ChR2) or inhibitory opsin (eNpHR3.0) enables the expression and transportof opsins to the nerve endings that innervate the hind paw. (b) Transdermal illumination with blue light causes pain associated behaviors (flinching, paw licking, vocalization) in ChR2+ mice. Transdermal illumination with yellow light raises the threshold for pain in eNpHR3.0+ mice.
(Image credit: Clifford J. Woolf et al./Nature Biotechnology)

Several weeks after injection, in response to blue light, excitatory opsin injected mice (ChR2+) showed distinct pain associated behaviors, flinching, vocalizing or licking their paws.A lower intensity blue light did not induce pain-related behaviors, but made ChR2+ mice sensitive to normally inoffensive mechanical and thermal stimuli. What's more, in the conditioned place preference experiment, ChR2+ mice showed significant aversion to low-level blue light emitting chamber and preference to stay in red light emitting chamber. In contrast, when exposing to yellow light, inhibitory opsin injected mice (eNpHR3.0+) were less sensitive to mechanical and thermal stimuli. It seems that shining of yellow light makes them oblivious of the pain. Most interestingly, the researchers tested if inhibition of nociceptors could alleviate neurotrophic pain. To do this, they used mice with a chronic constriction injury of sciatic nerves (CCI), these mice are hypersensitive to mechanical and thermal stimuli. But eNpHR3.0+ mice did not show this hypersensitivity when exposing to yellow light, meaning that this approach could inhibit neurotrophic pain.

Remarkably, instead of previous implantable light delivery devices, this method used transdermal illumination of lights, thus may provide a noninvasive treatment for pain. However, there still remain unsolved problems before bringing this treatment from lab to clinic and from mouse to human.For example, the skin is thicker in human than mouse and this may affect the light delivery, what's more, in this study, opsin expression decreases over several weeks, so more persistent opsin expression is needed for treatment of chronic pain.Nevertheless, this study opens the door to a completely new approach for a huge public health issue, and hopefully, one day a simple hand-held flashlight device will help people who suffer from chronic, debilitating pain.

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Iyer, Shrivats Mohan, Kate L. Montgomery, Chris Towne, SooYeun Lee, CharuRamakrishnan, Karl Deisseroth, and Scott L. Delp. "Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice." Nature biotechnology 32, no. 3 (2014): 274-278.