The opioid crisis in the United States has inflicted immeasurable suffering on individuals and communities, emphasizing the urgent need for alternative pain management solutions. The quest for non-opioid treatments is of paramount importance, not only to mitigate the risks of addiction and overdose, but also to devise pain relief strategies that remain effective without engendering tolerance and other challenging side effects in patients.

Recent research from the University of Chicago has pinpointed an alternative neural pathway in mice that provides pain relief, even in animals that have developed a tolerance to opioids. Published in Neuron in September, the study also demonstrated that pain relief through this pathway did not lead to tolerance, withdrawal symptoms upon cessation of treatment, or activation of reward systems. This significantly reduces the risk of addiction, offering a promising avenue for the development of effective, non-opioid pain relief.

“We have various categories of non-opioid treatments, but regrettably, nothing currently matches the potency of opioids in pain relief,” remarked Dr. Daniel McGehee, Professor of Anesthesia and Critical Care at UChicago and the senior author of the study. “Any alternative is a welcome option, and we have identified pain control circuitry here that can yield relief akin to opioid activity, but without the drawbacks.”

The ventrolateral periaqueductal gray (vlPAG) is a crucial hub in the brain overseeing pain regulation. Prior research has shown that interventions like electrical stimulation and pharmaceutical treatments targeting this region can alleviate pain. However, the non-opioid circuits that influence pain through modulations in vlPAG activity have received less scrutiny. One such circuit involves the neurotransmitter acetylcholine, which affects activity in various brain regions. While targeting acetylcholine receptors can alter pain responses, the mechanisms governing how naturally produced acetylcholine regulates pain control in the vlPAG had remained unexplored.

Dr. McGehee and Dr. Shivang Sullere, a former graduate student in the Committee on Neurobiology at UChicago and the first author of the study, delved into understanding how acetylcholine is released in this brain region under different pain states. They discovered that stimulating the ⍺7 receptor with a specific drug in mice led to a prolonged analgesic effect, despite the receptor’s usual role as an excitatory agent. This was a surprising and significant finding.

When the team tested the effects of elevating acetylcholine levels in mice with opioid tolerance, they observed the same enduring analgesic effects. This is because the acetylcholine pathway operates independently from the opioid system, so tolerance in one does not affect the effects of the other. Additionally, the animals did not exhibit signs of dependence or a preference for environments where they received the drug, indicating a lack of addictive properties.

Furthermore, imaging experiments revealed that heightened activity in ⍺7-expressing cells correlated with increased pain levels in the animals. When these cells were suppressed, pain was diminished.

Dr. Sullere noted, “Not only do these cells alleviate pain, but they also accurately reflect the pain state of the organism. Through imaging techniques, we can reliably monitor these neurons and acetylcholine in the vlPAG. This provides us with a valuable biomarker for the pain state of an organism. This unexplored role of acetylcholine also points towards its potential involvement in the central sensitization processes that contribute to the development of chronic pain conditions. Modifying acetylcholine signaling provides an opportunity to relieve pain and prevent the establishment of the chronic pain state.”

These findings offer multiple avenues for the development of new pain-relieving medications, whether by stimulating the release of acetylcholine or targeting ⍺7 receptors. Dr. McGehee emphasized that while medications targeting these receptors have been explored for various diseases, they have not yet been investigated extensively as painkillers.

“This is a potentially valuable target for new development of analgesics,” he stated. “We see that inhibiting these cells is important in terms of controlling pain, and it’s a very profound mechanism that works beautifully and to a similar degree to what we see with opioids.”

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