Opioid pain medication
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In work that could lead to a non-addictive alternative to opioids, scientists used chemogenetics to quiet hyperactive neurons that cause chronic pain in both mouse and cultured human neurons. Using a viral vector, they delivered PSAM4-GlyR—a fully humanized protein that consists of a chloride channel that can be activated by varenicline, a drug that is already approved.

The work was published in Science this week (Oct.4). The lead author is Jimena Perez-Sanchez, PhD, Nuffield Department of Clinical Neurosciences, University of Oxford. The senior author is David L. Bennett, MD, PhD, also of that department at Nuffield.

Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Most drugs currently used for the treatment of pain bind to receptors that are widely expressed in the peripheral and central nervous systems, and frequently associated with adverse effects.

Chronic pain affects around one in five adults in Europe alone. Opioids  are still the most effective drugs available for pain relief, but they come with serious side effects such as tolerance, addiction, and a risk of overdose.

Through chemogenetics, scientists can deliver engineered ligand-sensitive molecules to certain cells and then analyze the cells’ response to specific small molecules. Chemogenetics has shown promise as a means to suppress hyperexcitability in neurons, yet it is challenging to create such systems suitable for human applications.

“I think the challenge is delivering the chemogenetic receptor to humans.” Bennett told Inside Precision Medicine. “Gene therapy using viruses are available but to deliver to humans we would need to find the optimum route of delivery. It needs to be a fully human protein to prevent am Immune response.”

In this study, Bennett and his colleagues took mouse sensory neurons and applied PSAM4-GlyR—a modular system based on the human α7 nicotinic acetylcholine and glycine receptors. PSAM4-GlyR responds to inert chemical ligands and the clinically approved drug varenicline. Treating these neurons with varenicline, the team found, could inhibit their excitability.

Furthermore, the same approach relieved acute and inflammatory pain in mice that received injections of PSAM4-GlyR into clusters of neurons. Stable expression of the channel led to similar reversible suppression of pain-related behavior in mice even after 10 months of viral delivery.

The treatment also lowered the excitability of sensory neurons derived from human stem cells and suppressed spontaneous activity in neurons from a patient with erythromelalgia, which causes burning pain in people.

“The advantages of this system are that it is a fully humanized protein and it is designed to respond to a non-toxic drug which is already approved,” said Bennett.

The researchers note that chemogenetic approaches remain largely untested in humans, but speculate that the technique is viable because viral vectors have an established safety record.

“One thing that we would really like to focus on is to try and find ways of targeting this just to those sensory neurons that carry signals that drive pain leaving those neurons that carry information relating to light touch, warmth and cool unchanged,” said Bennett. “We would also like to optimize delivery to sensory neurons.”

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