Brain ‘circuit’ that turns stress into pain relief

Bengaluru: Scientists from centre for neuroscience at Indian Institute of Science (IISc) have discovered a remarkable brain circuit that can transform the stress of being physically restrained into pain relief.
Published in the journal “eLife”, the study reveals that neurons in the dorsal lateral septum (dLS), a small region in the forebrain, play a crucial role in this process.
The team, comprising Devanshi Piyush Shah, Pallavi Raj Sharma, Rachit Agarwal, and Arnab Barik, meticulously mapped out a neural network that connects pain and stress in the brain, shedding light on the intricate relationship between these two clinically challenging conditions.
While it is well-established that chronic pain patients often grapple with elevated stress and anxiety levels, which can further exacerbate their pain, the exact mechanisms underlying this vicious cycle have remained poorly understood until now, researchers said.
Now, employing cutting-edge mouse genetic and optogenetic techniques, researchers have identified a neural pathway that spans from lateral septum to the spinal cord, involving key regions in the hypothalamus and brainstem nuclei. They found that when mice were physically restrained, these inhibitory dLS neurons became highly active whenever the animals struggled to escape. Paradoxically, this increased dLS activity led to a reduction in pain sensitivity, raising pain tolerance levels. “It was surprising to find the dLS neuronal activity ramps up specifically during the struggle bouts when the mice are trying hard to get away. We showed this dLS activity is both necessary and sufficient for stress-induced analgesia to occur,” said Devanshi Shah, the first author of the paper.
The dLS neurons send projections to the lateral hypothalamic area (LHA), where they synapse onto excitatory LHA neurons. Remarkably, when the mice struggled under restraint, these excitatory LHA neurons were initially active but then, rapidly inhibited shortly after. This appears to be the critical step that triggers downstream analgesia by reducing the excitability of pro-nociceptive neurons in the rostral ventromedial medulla, a key region for relaying pain signals to the spinal cord.
“This work provides invaluable insights into neural underpinnings of how stress can exacerbate chronic pain and paves the way for development of novel therapeutic approaches that could help mitigate stress-induced exacerbation of chronic pain conditions,” said Arnab Barik, highlighting the far-reaching implications of their findings.