Newly Studied Pain Pathway May Provide Pain Relief Without Opioid Side Effects Interview with:
Daniel McGehee, PhD
Chair, Committee on Neurobiology
Department of Anesthesia & Critical Care
University of Chicago What is the background for this study?

Response: Chronic pain conditions are major challenges for those suffering with pain and the clinicians who struggle to find effective treatments. Identifying novel strategies for relieving pain will help limit availability of opioid drugs, as they offer alternatives to replace or reduce opioids in the clinic. 

Along with overdose and addiction issues, there are other complications and side effects of opioids, including tolerance, where the pain relieving properties diminish with repeated use, hypersensitivity to pain when patients stop taking the drug, constipation, and other peripheral side effects. 

Pain relief without those side effects would certainly be valuable for individuals struggling to treat painful conditions. What are the main findings? Are there medications which can modify acetylcholine signaling?

Response: The main findings of our study are that acetylcholine signaling has profound analgesic effects, and baseline and when the pathways is activated experimentally.  Interestingly, acute and chronic pain conditions suppress acetylcholine release in these pain control pathways.  That suppression of acetylcholine levels contributes to the hypersensitivity that individuals experience under chronic pain conditions such as injury or inflammation.   

When the acetylcholine inputs are stimulated, they activate a nicotinic acetylcholine receptor that typically causes excitation, but we were surprised to find that these receptors are actually inducing a persistent inhibition of the neurons in the pain control pathway.  That unexpected effect means that acetylcholine is having the same effect as opioid drugs, which also inhibit this same population of cells. 

We also tested several days of repeated stimulation of this cholinergic pathway or exposure to a drug that targets this acetylcholine receptor and did not see evidence of tolerance to the pain-relieving effects.  And as the title of our study indicates, this analgesic effect remained even after development of tolerance to opioids.  It was truly exciting to learn that this method for relieving pain does not have many of the side effects associated with opioid analgesic drugs. 

One final observation from our study is that monitoring the activity of the neurons that are inhibited by acetylcholine may provide an independent assay for the pain state of an animal or a person.  Assessing pain objectively is a challenge for neuroscientists as well as clinicians, and this could help alleviate that challenge.  

Drugs that target acetylcholine receptors have been tested in pain studies, but side effects have precluded their use for pain relief in people.  The alpha7 nicotinic receptors that we examined in this study may be a viable target for treating pain, but that has not been investigated to date.  We are also investigating methods to activate the acetylcholine inputs to the pain control pathways selectively, which could limit the side effects of targeting receptors that may have other physiological effects. What should readers take away from your report?

Response: Greater understanding of the role of acetylcholine in controlling pain signaling may novel identify novel analgesic drugs or treatment strategies to reduce the suffering of individual struggling with chronic pain and reduce the use of opioid drugs. What recommendations do you have for future research as a result of this study?

Response: Specifically, it will be important to explore the brain areas and neurotransmitters that control the activity of acetylcholine inputs to the pain control pathways.  More generally, we know that painful conditions vary widely with mood, environment, or activity, and it is important that we explore how our nervous system alters our perception of pain.   

Thank you for your interest and thanks to the National Institutes of Health for supporting this work.  None of the authors of this study have personal or financial conflicts of interest. 

Citation: Daniel S McGehee, A cholinergic circuit that relieves pain, despite opioid tolerance, Neuron (2023). DOI: 10.1016/

The information on is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

Last Updated on September 21, 2023 by