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Cholinergic signaling in the brain may offer scientists an alternative pathway to target to treat chronic pain.

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A surprising pathway to pain relief

A promising relationship between acetylcholine signaling and pain relief in mice could point the way to a non-opioid therapeutic.
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To treat chronic pain, doctors often prescribe opiates that are effective in the short term but highly addictive and problematic for long-term pain relief. Prescription opiates and their misuse has led to a high incidence of overdose deaths and contributed to the ongoing opioid overdose epidemic (1). This crisis has created an urgent need for new non-opioid options to treat chronic pain. 

In a study published in Neuron, researchers led by neuroscientist Daniel McGehee at the University of Chicago discovered an unexpected inverse relationship between pain and acetylcholine signaling (2). Their findings reveal an alternative pathway for pain relief that could be targeted in the development of non-opioid drugs. 

Multiple brain regions are involved in the perception and response to painful stimuli, including the ventrolateral periaqueductal gray (vlPAG) (3). Opioids provide analgesic effects in part by activating opioid receptors on vlPAG neurons (4). These same neurons also contain nicotinic acetylcholine receptors (nAChRs) that acetylcholine activates. While nAChRs are involved in pain processing, their role in pain relief is not well understood (5). McGehee and his team sought to change that and uncover the relationship between acetylcholine signaling and pain relief in the vlPAG. 

“My student came to the lab and said he wanted to look beyond the receptor and ask the question of how is this system activated endogenously? He was interested in acetylcholine as a potential modulator of pain.”

To explore the role of acetylcholine signaling, McGehee’s team used gene-targeted biosensors and in vivo imaging techniques to measure changes in acetylcholine release in the vlPAG of animals experiencing acute versus chronic pain. To their surprise, they found that both acute and chronic pain caused a decrease in acetylcholine release in the vlPAG. “In most other areas of the brain where acetylcholine is released, we see evidence of increased acetylcholine with salient stimuli,” said McGehee. “But here, we saw the opposite.”

After revealing this peculiar relationship between acetylcholine and pain in the vlPAG, McGehee’s team aimed to identify not only the source of vlPAG acetylcholine release, but also how acetylcholine might contribute to pain relief. Through a series of experiments using anatomical labeling, the researchers found that a major source of acetylcholine to the vlPAG came from neuronal cell terminals in the brain region called the pedunculopontine tegmental nucleus (PPTg), revealing a vlPAG-PPTg circuit of interest. With the circuit identified, they went on to investigate its analgesic potential. In mice with chronic pain, they found that stimulating the circuit increased acetylcholine release and reduced the animals’ abnormal sensitivity to harmless physical stimuli, which is a common symptom of chronic pain. 

The team then went one step further to find out whether a specific receptor was involved in this circuit’s pain relief mechanism. With more digging, the team found that vlPAG neurons contain alpha7 nAChRs. Activation of these receptors unexpectedly caused a decrease in neuronal activity. Stopping the activity of these neurons led to pain relief in animal models of chronic pain. Marina Picciotto, a nicotinic acetylcholine receptor researcher at Yale University who was not involved in the study, said that was “one giant surprise.” She explained that previous cellular studies have shown that nAChRs usually increase the activity of neurons. “In this case, this is a really paradoxical finding that the alpha7 agonist is potentially decreasing the activity of the cells in which it's expressed. That's huge. It's a big, big deal.” 

The fact that nAChRs are acting unexpectedly in this mechanism of pain relief reveals that these receptors are more complicated than previously understood. This opens up a new avenue for further study into unique functions of different types of nAChRs, which could lead to more precise targeting for chronic pain treatments.

With this alternative circuit and its mechanism revealed, McGehee’s team went on to compare alpha7 nAChR activation to morphine, a commonly used opioid treatment for chronic pain. They found that EVP-6124, an alpha7 nAChR agonist, produced analgesic effects similar to morphine, but EVP-6124 did not induce tolerance, reward preference, or withdrawal symptoms characteristic of opioids. 

Questions still remain as to how translational these results will be in developing new treatments for chronic pain. Widespread activation of nAChRs in the body may lead to unwanted side effects. “Both [of the main acetylcholine] receptors are expressed widely, and they are absolutely contributing to every organ system in our body,” said McGehee. “That has actually interfered with the advancement of other nicotinic drugs from animal studies where the efficacy was similar to morphine.” 

Even though nAChR drug development poses these problems, McGehee and his team still have hope. Other research groups have explored alpha7 nAChRs as a target for cognitive improvement in patients with schizophrenia (6). While the effectiveness of these drugs for cognitive improvements are still unclear, the drugs passed safety testing. McGehee would like to work with these drugs in mouse models of chronic pain in the near future.

Moving forward, the team plans to explore acetylcholine interactions with other neurotransmitters or molecules related to pain relief. They are specifically interested in cannabinoids, biological compounds that bind to cannabinoid receptors and play a role in homeostasis throughout the body (7). Cannabinoid receptors are also expressed on the same vlPAG neurons with alpha7 nAChR receptors and may influence cholinergic mechanisms (2). “We've got this convergence of modulatory systems. ... We're excited about that overlap, and how can we potentially exploit these systems,” McGehee said. "What if we did a combination therapy that actually limited all the side effects and relieved pain in an efficacious way?” 

References 

  1. CDC. Understanding the Opioid Overdose Epidemic. Overdose Prevention https://www.cdc.gov/overdose-prevention/about/understanding-the-opioid-overdose-epidemic.html (2024).
  2. Shivang, S., Kunczt, A., & McGehee, D.S. A cholinergic circuit that relieves pain despite opioid tolerance. Neuron  111, 3414-3434 (2023).
  3. Mokhtar, M. & Singh, P. Neuroanatomy, Periaqueductal Gray. StatPearls (StatPearls Publishing, 2024).
  4. McPherson, K.B. & Ingram, S.L. Cellular and circuit diversity determines the impact of endogenous opioids in the descending pain modulatory pathway. Front Syst Neurosci  16 (2022).
  5. Naser, P.V. & Kuner, R. Molecular, cellular and circuit basis of cholinergic modulation of pain. Neuroscience  387, 135-148 (2018).
  6. Tregellas, J.R. & Wylie, K.P. Alpha7 Nicotinic Receptors as Therapeutic Targets in Schizophrenia. Nicotine & Tobacco Research  21, 349-356 (2019).
  7. Sheikh, N. K. & Dua, A. Cannabinoids. StatPearls (StatPearls Publishing, 2024).

About the Author

  • A headshot of a woman smiling and wearing a floral shirt and white lab coat.
    Gabriela Lopez is a neuroscience PhD candidate at Northwestern University and an intern at Drug Discovery News. She earned her master’s degree from Northwestern University in 2021 and currently studies the role of the dopamine system in avoidance learning.

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