New Insight into Brain Circuits Offering Potential for Improved Pain Relief

Researchers have identified a specific neural pathway in the brain that plays a crucial role in suppressing pain during threatening or fear-inducing situations. Published as a reviewed preprint in eLife, this study enhances our understanding of fear-conditioned analgesia—the natural reduction of pain experienced when an individual perceives danger. The research was conducted in mice and highlights the importance of the periaqueductal gray matter (PAG), particularly its ventrolateral region (vIPAG), which integrates signals from fear-related brain areas and projects to the spinal cord via the rostral ventromedial medulla (RVM) to modulate pain. Co-lead author Nanci Winke explained that the vIPAG is strategically situated to influence emotional regulation of pain, although the specific neuronal circuits involved remained largely unknown until now.

The study involved conditioning mice to associate an auditory cue with a frightening event and observing delayed pain responses when exposed to the threat, indicating analgesia triggered by fear. Using optogenetics, the team identified somatostatin-expressing interneurons within the vIPAG as key modulators of this effect. Suppressing these SST-positive cells delayed pain responses, while activating them increased pain transmission at the spinal cord level. Neural tracing further revealed that these cells connect to RVM neurons, which project to the spinal cord’s pain regulatory regions.

The findings suggest that this brain circuit simultaneously influences fear expression and pain suppression, potentially linking emotional states like anxiety and chronic stress to pain perception. Co-senior author Cyril Herry emphasized the significance for understanding pain and emotional regulation, pointing to future research to explore how negative emotional conditions alter this circuitry and how insights could lead to targeted analgesic therapies. Further studies are necessary to determine whether similar mechanisms operate in humans and across different emotional contexts.

This discovery provides valuable insight into the neural basis of fear-related pain modulation and opens avenues for developing new pain management strategies that consider emotional influences on pain perception.