For years, scientists have entertained the idea that a common lab technique called chemogenetics might eventually help patients. The technique allows investigators to precisely manipulate and then study cells using engineered proteins. If harnessed correctly by the pain field, chemogenetics could possibly become a treatment for chronic pain.
Now, an animal study shows the promise of chemogenetics, as well as the obstacles it still faces. David Bennett, a pain researcher at the University of Oxford, UK, and colleagues modified a protein and then inserted it into nerves that had been experimentally damaged in mice. Upon activating the protein with a non-toxic drug called ivermectin, the researchers could silence the electrical activity of nerve cells. What’s more, doing so diminished the pain-related behavior seen in animals with nerve injury.
Rebecca Seal, a pain researcher at the University of Pittsburgh who was not involved in the study, says the chemogenetic strategy has clear potential to help patients. “It has advantages over some of the efforts people are thinking about, such as optogenetics,” which uses light to either excite or inhibit neurons but so far has usually required implanting a device to deliver the light (see RELIEF related interview).
The results were published in the October issue of the journal Brain.
Chemogenetics for pain relief
Bennett and his colleagues have been trying to better understand the contribution of the peripheral nervous system to pain. And so, “we were interested in ways of switching off populations of sensory neurons,” he says. Sensory neurons are nerve cells that convert a stimulus in the external environment into an electrical signal.
Ultimately, they landed on chemogenetics. “It allows you to control activity in neurons, hopefully in a rapid and reversible fashion,” Bennett says. The particular protein they used in the study, called GluCl, can interfere with the generation of electrical signals, dampening the communication between nerve cells.
Following a nerve injury, sensory neurons send far more signals to the central nervous system (spinal cord and brain), leading to so-called neuropathic pain. So, to quiet those cells, the investigators used several genetic tricks to get them to make GluCl. Then, they injected injured animals with ivermectin, a drug that attaches to and activates the engineered protein. In response, sensory neurons containing GluCl fell silent.
Consistently, activating GluCl in injured mice lessened two pain-related behaviors. Without GluCl, animals developed exaggerated responses to both harmless touch and mild cold. But after receiving ivermectin, mice with GluCl showed a reduction in such hypersensitivity, an effect that lasted for two days. “That time course could have a therapeutic advantage,” says Seal.
The right type of neuron
Though in its early days, the new approach could, in principle, outperform commonly prescribed drugs in alleviating neuropathic pain. “On a global level, we’re still under-resourced in the treatments we have available to us,” says Bennett.
Still, there could be side effects. In the study, GluCl was delivered to a large swath of sensory neurons, consisting of many different types of cells. And while uninjured animals with the protein moved normally and seemed to be aware of their movement (an important sense known as proprioception), deficits in touch, pain, and heat sensation did emerge in these healthy mice.
“Ideally, one would want to target peripheral neurons without dramatically affecting acute sensations but how to achieve this is still not clear,” says Seal.
To Bennett, the study is a “proof-of-concept,” and he thinks that much work needs to be done in animals before trying it in people.
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman