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A newly discovered brain pathway in mice may contribute to the development of opioid tolerance, suggesting that future therapies targeting this pathway could prevent opioid addiction and overdose.

Opioids like morphine, oxycodone and fentanyl are effective painkillers, but also highly addictive as frequent use necessitates increasingly larger doses to achieve the same effect. This raises the risk of overdose, which is a growing problem in the US: in 2020, nearly died from opioid overdose in the country.

鈥� and some 鈥� suggest that opioid tolerance develops more quickly , a process called associative learning. For example, if someone takes a certain dose of oxycodone every day in their bedroom, but then takes that same dose in another environment for the first time, their tolerance can decrease. That difference can significantly increase the risk for overdose, says Wei Xiong at the University of Science and Technology of China in Hefei.

To identify the mechanism behind this phenomenon, he and his colleagues analysed the brains of 24 mice given daily morphine injections for five days. Half the mice received injections in their home cage, while the other half received them in a separate cage with striped walls. The researchers anticipated that mice in the latter group would develop a greater tolerance to morphine because they learned to associate the striped cage with the drug, whereas mice in the control group wouldn鈥檛 have such a strong association because their home cage is linked to multiple activities like sleeping and eating and not just the drug. As expected, mice聽in the striped-cage group developed greater opioid tolerance than those in the control group, as measured by how soon they retracted their paw from heat while on morphine.

The researchers then injected the mice with a solution that binds to a protein associated with recent neuron activity. After euthanising the mice, the team viewed slices of their brains under a microscope and shone fluorescent lighting on the samples, which caused the solution to glow. This allowed the researchers to identify which brain regions had been most active. Compared with mice in a control group, those in the striped-cage group displayed signs of greater brain activity in three regions: the ventral hippocampus, dorsomedial prefrontal cortex and basolateral amygdala. These areas are known to be involved in memory, self-awareness and pain regulation, respectively.

In subsequent experiments with mice who developed opioid tolerance through associative learning, the researchers homed in on the specific neurons connecting the three regions. The team then used a technique known as chemogenetics to activate or deactivate cells in this pathway using drugs. After four days of morphine injections, mice with the active pathway had nearly four times the tolerance to the drug compared with mice without the active pathway. This indicates that the newly identified pathway between these three regions governs the development of opioid tolerance in response to contextual cues, says Xiong.

at the National Institute on Drug Abuse in Washington DC says these findings challenge the idea that opioid tolerance is mostly due to brain receptors becoming less sensitive to the drug: 鈥淭his [paper] says it鈥檚 much more than that.鈥�

If a similar pathway exists in humans, we could develop therapies to inhibit it, potentially reversing tolerance in people addicted to opioids and possibly preventing addiction in people prescribed these medications, says Volkow. Doing so would potentially save thousands of lives.