By Matt Wood
The opioid epidemic in the United States has exacted an incalculable toll on individuals and communities, creating an urgent need for alternative painkillers. The search for non-opioid treatments is crucial, not only to mitigate the risks of addiction and overdose but also to develop pain management tools that remain effective without inducing tolerance and other challenging side effects in patients.
New research from the University of Chicago identified an alternative signaling pathway in the brain of mice that relieves pain, even in animals that have developed tolerance to opioids. The study, published in Neuron in September, also showed that pain relief through this route did not induce tolerance, did not create withdrawals symptoms after treatment was stopped, and did not activate reward systems, limiting risk for addiction and making it a viable path to developing effective, non-opioid pain relief.
“There are multiple categories of non-opioid treatments, but the bad news is that nothing currently compares to opioids for the level of pain relief,” said Daniel McGehee, Ph.D., Professor of Anesthesia and Critical Care at UChicago and senior author of the new study. “Any alternative is a welcome option, and we have found pain control circuitry here that can produce relief similar to what we see with opioid activity, without the downsides.”
A different circuit for pain relief
The ventrolateral periaqueductal gray (vlPAG) is an area of the brain that serves as an important crossroads of systems that control pain. Previous research has shown that electrical stimulation and pharmacological treatments targeting this region can relieve pain, although the non-opioid circuits that alter pain through changes in activity in this part of the brain are less well-studied. One of these circuits involves the neurotransmitter acetylcholine, which affects activity in multiple parts of the brain. Targeting acetylcholine receptors can change pain responses, but the mechanisms by which naturally produced acetylcholine regulates pain control circuitry in the vIPAG had not been explored.
McGehee and Shivang Sullere, Ph.D., a previous graduate student in the Committee on Neurobiology at UChicago, now a postdoctoral scholar at the Harvard Medical School and the new study’s first author, investigated the dynamics of how acetylcholine is released in this area of the brain under various pain states, like inflammation, chronic neuropathy, or acute pain. McGehee’s lab published a paper in 2017 showing that targeting an acetylcholine receptor in the vIPAG called alpha-7 (⍺7) produced an analgesic effect. One might expect that the body would take advantage of this and release more acetylcholine in a painful scenario, but instead, the researchers saw the opposite effect—it was being suppressed. The team then set out to understand how and why this was happening.