Researchers in Canada have identified a brain circuit in mice that causes negative experiences to amplify pain, which could help develop better therapies to reduce pain.  

Clinicians have observed that negative expectations, experiences and fear can worsen pain symptoms and treatment effectiveness, a phenomenon known as the ‘nocebo effect’. It is known that blocking the effect of a hormone called cholecystokinin (CCK) reduces pain, but what happens in the brain was not well understood, largely due to a lack of experimental models to study this effect.  

Researchers from EARA member University of Toronto and McGill University measured pain sensitivity, by determining the pressure necessary to apply to their hind paws to evoke a reaction, in mice exposed to environments where they had previously experienced pain caused by a small incision in their hind paw or constriction of the sciatic nerve. They also evaluated the effect of social context on pain sensitivity by placing mice near other animals experiencing pain. As in humans, drugs that block the effect of CCK reduced the nocebo effect elicited by previous experiences and social context in mice.  

By combining pharmacological approaches and optogenetics, a technique which can control brain activity with light, the researchers discovered that pain sensitivity depended on CCK release from neurons coming from the anterior cingulate cortex, a region involved in emotional and cognitive processing, to the lateral periaqueductal grey, which is involved in pain. 

“If we can better understand the circuitry that drives these effects, we may eventually be able to reduce harmful pain amplification in disorders where anxiety, anticipation, and negative expectations worsen symptoms,” said Loren Martin, researcher at the University of Toronto and a lead author of the study published in Nature Communications.