by Krissy Lyon

When you accidentally touch a hot stove, you pull your hand away almost immediately, thanks to a quick reflex informed by your body’s pain receptors. Pain is an essential feature of our bodies that alerts us to danger or injury. But imagine if you felt pain with no immediate source. What if this pain lasted for months or years? This condition, called chronic pain, is estimated to affect 100 million Americans. Researchers are still working to understand the neurobiology of chronic pain. Currently, we think it’s caused by overactivity of the neurons that process pain signals. With chronic pain, these pain signals persist much longer than normal following an injury or even with no injury at all.

Living with constant pain, chronic pain sufferers can find it difficult to sleep, exercise, and maintain relationships, which can lead to feelings of anxiety, stress, and depression. Doctors can prescribe a number of treatments for chronic pain including: over-the-counter medications like aspirin, pain relief creams, acupuncture, and narcotic pain medications like morphine. They may even prescribe antidepressants which are thought to work by altering levels of brain chemicals to control feelings of pain. Sadly, none of these methods work for every patient, and some patients must try many treatments before achieving relief. New and improved treatments are greatly needed. One exciting possibility for chronic pain treatment may come from optogenetics, a technology currently used by neuroscientists that employs light to control neuronal activity.

How does optogenetics work?

Optogenetics relies on light-responsive proteins called opsins to selectively turn neuronal activity on or off with a flash of light. When a neuron ‘fires’ (is active) it releases a chemical signal to communicate with the rest of the brain, called a neurotransmitter. Optogenetics controls whether or not this signal is sent. To understand how optogenetics does this, it is important to understand how neurons function normally (Figure 1). Whether or not a neuron fires depends on the flow of positively- or negatively-charged ions across the membrane. In general, when more positively charged ions enter, the neuron will fire. When more negatively charged ions enter, the neuron does not fire. Opsins play their role by controlling which ions enter the neuron.

Figure 1: Understanding neuronal activity. In general, more positive ions inside the cell relative to the outside result in the neuron firing and thus releasing neurotransmitter. When more negative ions are inside the cell relative to the outside the neuron does not fire thus no neurotransmitter is released. Positive ions represented as yellow circles with '+' sign, negative ions represented as yellow circles with '-' sign, green diamonds represent neurotransmitter.
Figure 1: Understanding neuronal activity. In general, more positive ions inside the cell relative to the outside result in the neuron firing and thus releasing neurotransmitter. When more negative ions are inside the cell relative to the outside, the neuron does not fire, so no neurotransmitter is released. Positive ions represented as yellow circles with ‘+’ sign, negative ions represented as yellow circles with ‘-‘ sign, green diamonds represent neurotransmitter.

Opsins come in two flavors: “on” and “off” (Figure 2). Channelrhodopsin, the most common “on” opsin, is found in algae but not in humans. When activated by blue light, channelrhodopsin lets positive ions enter the neuron. Conversely, halorhodopsin, the most common “off” opsin, lets negative ions enter the neuron when activated with yellow light. Halorhodopsin is also not found in humans but rather in single-celled organisms called Archaea. Yet, neuroscientists have inserted the genes for these “on” and “off” opsins into mice to control their neuronal activity using light.

Figure 2: How does optogenetics work? Left panel: Turning a neuron on. Blue light activates the 'on' opsin resulting in the neuron firing and releasing neurotransmitter. Right panel: Turning a neuron off. Yellow light activates the 'off' opsin preventing the neuron from firing.
Figure 2: How does optogenetics work? Left panel: Turning a neuron on. Blue light activates the ‘on’ opsin resulting in the neuron firing and releasing neurotransmitter. Right panel: Turning a neuron off. Yellow light activates the ‘off’ opsin preventing the neuron from firing.

How does this activation work? The activating light is delivered as a quick flash of light, around one second, using a ‘light pipe’ inserted through a hole in the skull to direct light to a specific area of the brain.  This technology has been useful for researchers studying neuronal connections and their functions in the brains of rodents and other research models.  However, recent advances are taking optogenetics to the clinical level. In the future, optogenetics might be a treatment for restoring vision, treating symptoms of Parkinson’s disease or turning off neurons that cause chronic pain.

Treating chronic pain with optogenetics

When it comes to using optogenetics in humans, you may be thinking, “Algae and Archaea have opsins, how do we get opsins into humans?” and “Would you have to walk around with a light source all the time?” These are the two major constraints for using optogenetics in clinical applications, but researchers are working towards solutions for these problems.

Towards delivering opsins to humans, Scott Delp’s laboratory at Stanford University has already used non-disease-causing viruses to deliver opsins to the sciatic nerve of mice. The genetic material required for a cell to make an opsin is packaged into a gutted virus that can deliver the opsin, but does not cause disease. Researchers then inject this virus into a target area and cells that take up the virus can then make opsins.

In studies of mice, researchers delivered an “on” opsin to pain processing neurons present in the paw of a mouse. When they activated the opsin noninvasively with light through the bottom of the cage, the mice experienced pain. Importantly, when researchers delivered an “off” opsin and activated it with light they were able to inhibit the perception of painful touch and heat sensitivity (Figure 3).

Figure 3: Turning on or off pain processing neurons. Left panel: Turning on pain processing neurons through light-activation of excitatory 'on' opsin results in the mouse feeling pain. Middle panel: Turning off pain processing neurons through light-activation of inhibitory 'off' opsin results in the mouse becoming less sensitive to pain. Right panel: Turning off pain processing neurons in a mouse with chronic injuries, thought to model human chronic pain, results in the mouse becoming less sensitive to painful touch or heat suggesting that optogenetics may work for treatment of chronic pain.
Figure 3: Turning on or off pain processing neurons. Left panel: Turning on pain processing neurons through light-activation of excitatory ‘on’ opsin results in the mouse feeling pain. Middle panel: Turning off pain processing neurons through light-activation of inhibitory ‘off’ opsin results in the mouse becoming less sensitive to pain. Right panel: Turning off pain processing neurons in a mouse with chronic injuries, thought to model human chronic pain, results in the mouse becoming less sensitive to painful touch or heat suggesting that optogenetics may work for treatment of chronic pain.

These exciting experiments raise the question of whether optogenetics could be used to turn off overactive pain processing neurons in people with chronic pain. In this same study, researchers delivered the “off” opsin to mice with chronic injuries. These mice are more sensitive to painful touch and heat than normal mice and are thought to model some aspects of chronic pain in humans. Activation of the opsins, which turned off the pain processing neurons, reduced the mice’s sensitivity to painful touch and heat. These experiments demonstrate that optogenetics may have potential to treat chronic pain.

In these mouse experiments, the light was delivered through the bottom of the cage allowing the mice to move around freely. However, it would be more convenient for humans if they could easily carry the light source with them. Towards this goal, the laboratories of Robert Gereau and Johns Rogers have collaborated to develop an implantable system for wireless delivery of light to the spinal cord and peripheral nervous system. This system is lightweight and flexible, making it ideal for potential optogenetic therapies.

A future for optogenetics to treat human chronic pain

Circuit Therapeutics, founded by Scott Delp and other neuroscientists, is developing technologies based on optogenetics to treat chronic pain in humans. They aim to use a similar viral approach to target opsins to specific neurons and neural circuits and then apply light to that area to control pain. Circuit Therapeutics recently received a 2.7 million dollar contract from the Defense Advanced Research Projects Agency (DARPA) for development of optogenetic therapeutics in the peripheral nervous system and chronic pain.

Optogenetics is an exciting possibility for future treatment of chronic pain, but there are many questions that remain to be answered. For example, it’s unclear if patients should expect to undergo treatment with light for their entire lives or if optogenetics could cure their chronic pain for good after a few treatments. With more research into this technology, optogenetics may one day provide long-lasting and efficient treatment for the many people who suffer from chronic pain.

Krissy Lyon is a PhD candidate in Neuroscience at Harvard University.

This article is part of the April 2016 Special Edition on Neurotechnology.

For more information:

The development of optogenetics: http://www.newyorker.com/magazine/2015/05/18/lighting-the-brain

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