The world has changed since 1664, when the French philosopher and scientist René Descartes first claimed that the brain was responsible for the sensation of pain.
However, a key question remains: how exactly does the human brain work? feel pain? Specifically, thermal pain, such as that felt when touching an open flame or hot pan while cooking.
A team of researchers from the Department of Neurosciences of the Case Western Reserve University School of Medicine think they’ve found an answer – that a neural circuit involving spinal neurons and a signaling pathway – is responsible for how searing pain is felt.
They believe their discovery, recently published in the journal neuron, could lead to more effective treatment of pathological chronic pain, such as shooting, stabbing, and burning pain, because it may involve the same signaling pathway.
“We know that heat, cold, pressure and itching of our skin leads to appropriate sensations in the brain. However, the neurons encoding thermal signals in the spinal cord were unclear,” said Hongsheng Wang, lead study author and postdoctoral fellow at the School of Medicine. “Our study identified a group of interneurons in the spinal cord necessary for heat sensation. We also found that a signaling pathway contributes to heat hypersensitivity caused by inflammation or nerve damage.
The study
The brain controls everything we do, from how we perceive the world around us to how we move our bodies and experience sensations. The process involves neurons, which are cells that act as messengers to transmit information between the brain and the nervous system. Neurons send information through complex circuits throughout the body.
The research team examined spinal cord neurons and their role in thermal pain by analyzing mouse models and their response to hot plates. During this process, the team identified the activation of a “new” or newly discovered class of spinal cord neurons (called ErbB4+) that process heat signals to the spinal cord.
The team wanted to dig deeper into whether these neurons are specifically responsible for thermal pain. There are several ways to test this, including killing ErbB4+ neurons.
The researchers expressed a toxin specifically targeting ErbB4+ neurons. Once the neurons were destroyed, the pain response to heat was impaired. This demonstrated that ErbB4+ neurons are specifically linked to how thermal pain is sensed, and when destroyed, pain is no less felt.
They also looked at the role of neuregulin 1 (NRG1), a protein involved in many cellular functions. They found that NRG1 and its receptor tyrosine kinase ErbB4 (often referred to as NRG1 signaling) are also involved in thermal pain sensation.
The results
“Pain is a feeling that we have all experienced. For most of us, pain is temporary,” said Lin Mei, professor and chair of the School of Medicine’s Department of Neuroscience and corresponding author of the study. “However, for patients with pathological pain, the experience of pain is endless, with little hope of relief. Scientists have long believed it to be the result of dysfunctional neural activity.
Mei said their study showed that pathological pain can be reduced by injecting an ErbB4+ inhibitor or an NRG1 neutralizing peptide.
The application of these findings may go beyond the therapeutic treatment of pathological pain.
“NRG1 and ErbB4 are risk genes for many brain disorders, including major depression and schizophrenia,” Mei said. “Further studies are warranted to show whether the mechanism of heat pain and pathological pain also plays a role in different types of pain experienced by those with brain disorders.”
Reference: Wang H, Chen W, Dong Z, et al. A new connection of spinal neurons for heat sensation. neuron. 2022. do: 10.1016/j.neuron.2022.04.021
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