A team of Bio-X researchers at Stanford has developed mice whose sensitivity to pain can be dialed up or down simply by shining light on their paws.

The research could help scientists understand and eventually treat chronic pain in humans.

The mice in Scott Delp’s lab, unlike their human counterparts, can get pain relief from the glow of a yellow light.

“This is an entirely new approach to study a huge public health issue,” Delp said. “It’s a completely new tool that is now available to neuroscientists everywhere.” He is the senior author of a research paper published Feb. 16 in Nature Biotechnology.

The mice are modified with gene therapy to have pain-sensing nerves that can be controlled by light. One color of light makes the mice more sensitive to pain. Another reduces pain.

Increasing or decreasing the sensation of pain in these mice could help scientists understand why pain seems to continue in people after an injury has healed. Does persistent pain change those nerves in some way? And if so, how can they be changed back to a state where, in the absence of an injury, they stop sending searing messages of pain to the brain?

Optogenetics applied to the peripheral nervous system



The researchers took advantage of a technique called optogenetics, which involves light-sensitive proteins called opsins that are inserted into the nerves. Optogenetics was developed by a colleague of Delp, Karl Deisseroth, a co-author of the journal article. He has used the technique as a way of activating precise regions of the brain to better understand how the brain functions. Deisseroth is a professor of bioengineering, psychiatry and behavioral sciences.

Delp, who has an interest in muscles and movement, saw the potential for using optogenetics for studying the many nerves outside the brain. These are the nerves that control movement, pain, touch and other sensations throughout our body and that are involved in diseases like amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease.

A key component of the work was a new approach to quickly incorporate opsins into the nerves of mice. The team started with a virus that had been engineered to contain the DNA that produces the opsin. Then they injected those modified viruses directly into mouse nerves. Weeks later, only the nerves that control pain had incorporated the opsin proteins and would fire, or be less likely to fire, in response to different colors of light.

The speed of the viral approach makes it very flexible, both for this pain work and for future studies. Researchers are developing newer forms of opsins with different properties, such as responding to different colors of light. “Because we used a viral approach we could, in the future, quickly turn around and use newer opsins,” said Montgomery, who is a Stanford Bio-X fellow.

Delp said there are many challenges to meet before results of these experiments — either new drugs based on what they learn, or optogenetics directly — could become available to people, but that he always has that as a goal.

Delp and Deisseroth have started a company called Circuit Therapeutics to develop therapies based on optogenetics.

Abstract of Nature Biotechnology paper

Primary nociceptors are the first neurons involved in the complex processing system that regulates normal and pathological pain1. Because of constraints on pharmacological and electrical stimulation, noninvasive excitation and inhibition of these neurons in freely moving nontransgenic animals has not been possible. Here we use an optogenetic2 strategy to bidirectionally control nociceptors of nontransgenic mice. Intrasciatic 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, allowing 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.