Suppressing Neurons Curbs Withdrawal-Induced Pain Hypersensitivity
Insights From Mouse Study Could Aid Treatment for Opioid Use Disorder
A headache or stubbed toe is annoying enough as it is, but for people in recovery from opioid use disorder, everyday aches and pains — and even sensations that would ordinarily not be painful at all — can be amped up to the point that they become quite distressing. A new IRP mouse study has helped scientists home in on the specific brain cells that might cause this phenomenon, providing a first step towards an intervention that could make it easier for people to stop using addictive opioid medications or illegal drugs like heroin.1
Doctors prescribe opioid medications to help patients deal with pain from an injury or surgery, and patients need to stay on them until the initial source of pain has healed. However, the longer someone continues using opioids, the more likely they are to go through withdrawal when they stop. This brings on a number of unpleasant symptoms that include increased sensitivity to pain, known as hyperalgesia.
“It’s very complicated for clinicians to address this issue because if they remove the opioids, then the original pain comes back, but if they maintain the treatment, there’s additional pain that is appearing,” explains Yocasta Alvarez-Bagnarol, Ph.D., who co-led the new study while conducting her doctoral research at NIH under the guidance of IRP senior investigator Marisela Morales, Ph.D., and IRP Stadtman Investigator Leandro Vendruscolo, Ph.D., Pharm.D.
“When people detox, they have physical withdrawal in the first few days or first week and then that resolves, but the hyperalgesia can last for up to two or three years after the end of exposure to opioids,” Dr. Vendruscolo adds.
Dr. Alvarez-Bagnarol began her doctoral research by examining which neurons in the brain show increased activity when mice go through withdrawal from opioids.2 Based on the results of those experiments, she and her colleagues decided to more closely examine cells in a part of the brain called the dorsal raphe nucleus.
In their new study, the IRP team discovered four types of neurons in the dorsal raphe nucleus that can be influenced by opioid molecules, since they have receptors for the molecules to bind to. However, when the scientists repeatedly gave mice an opioid drug over a period of several days and then withheld it, they found that only three of those sets of neurons were more active than they were in mice that had never been exposed to opioids. Slightly more than half of the neurons that became more active during opioid withdrawal were so-called ‘GABAergic’ neurons that use the chemical GABA to communicate with other cells, so the IRP team decided to focus on those in subsequent experiments.
The scientists next leveraged a cutting-edge tool called chemogenetics to inhibit only GABAergic neurons in the dorsal raphe. The technique uses a virus to deliver a gene for a specific, lab-designed molecular receptor into only the neurons that researchers want to manipulate in animal models. In this case, the receptor was ‘inhibitory,’ so the activity of the neurons would be dampened when the receptor was triggered. Once infected by the virus, neurons begin making the lab-designed receptor, which can only be triggered by treating the animals with a synthetic compound that doesn’t exist outside research labs — in this case, one called J60.
To figure out whether inhibiting GABAergic neurons in the dorsal raphe might affect withdrawal-induced hyperalgesia, the IRP researchers assessed pain sensitivity in mice that were experiencing the early stages of withdrawal from opioids and had been given the chemogenetic treatment. The test involved prodding the animals’ paws with increasing amounts of force using a small, harmless instrument. The lower the amount of force required to cause a mouse to withdraw its paw from the instrument, the more sensitive the animal is to pain.
The researchers found that mice going through opioid withdrawal were more sensitive to pain than mice that had never been exposed to opioids. However, when the researchers gave the synthetic J60 compound to mice going through opioid withdrawal that had received the chemogenetic treatment, the animals showed less pain hypersensitivity than mice experiencing withdrawal that were given J60 but did not have the lab-designed receptor in their brains.
“When I went to do the testing during the chemogenetic studies, the effects were really impressive,” Dr. Alvarez-Bagnarol recalls. “I have done a lot of hyperalgesia tests, so I kind of know how the animals behave, and I could see that this group of animals was really, really different.”
The study’s results point to the tantalizing possibility that inhibiting GABAergic neurons in the dorsal raphe somehow, such as with a specifically targeted medication, might combat the hypersensitivity to pain that people experience when they stop using opioids. It’s also possible that tamping down the activity of other types of neurons in the same brain region might have the same effect — a possibility that the study’s authors plan to examine in future experiments. Although a treatment that might have such effects in humans is a long way off, it would undoubtedly remove a major obstacle faced by people trying to stop using opioids.
“If people stop taking the drug for a long time, the brain will eventually recover, and although the withdrawal is long-lasting, it goes down over time,” Dr. Vendruscolo says. “If you can treat the negative emotional state of opioid withdrawal, that may give someone the opportunity to actually seek more treatment and start exercising the other domains that are affected by opioid dependence. They can start looking for a job again, they can start caring for their family, and they can find a purpose for their lives and so on. If you’re miserable, it’s much harder to do those things.”
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 Alvarez-Bagnarol Y, García R, Vendruscolo LF, Morales M. Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal. Neuropsychopharmacology. 2023 Aug;48(9):1300-1308. doi: 10.1038/s41386-023-01620-5.
 Alvarez-Bagnarol Y, Marchette RCN, Francis C, Morales M, Vendruscolo LF. Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice. eNeuro. 2022 Jul-Aug; 9(4): ENEURO.0106-22.2022. doi: 10.1523/ENEURO.0106-22.2022.
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This page was last updated on Tuesday, October 24, 2023