How Does Heat Cause Pain?

Fire Flame

The study identified the mechanism responsible for how thermal pain is sensed.

A signaling system involving neurons that are involved in how we comprehend thermal pain has been discovered by a new study.

The world has greatly evolved since 1664 when French philosopher and physicist Rene Descartes initially argued that the brain was responsible for experiencing pain.

However, one critical question remains: How does the human brain perceive pain? Specifically, thermal pain, the pain felt while touching an open flame or a hot skillet while cooking.

Researchers in the neurosciences department at Case Western Reserve University School of Medicine believe they have the answer; burning pain is sensed by a neural circuit made up of spinal neurons and a signaling pathway.

Because it could involve the same signaling pathway, they think their current discovery—which was published in the journal Neuron—could result in a more efficient treatment for chronic, pathological pain, such as shooting, stabbing, and burning pain.

“We know that heat, cold, pressure, and itching stimulations to our skin result in appropriate feelings in the brain. However, the neurons encoding the heat signals in the spinal cord were unclear,” said Hongsheng Wang, study lead author and a postdoctoral fellow at the School of Medicine. “Our study identified a group of interneurons in the spinal cord required for heat sensation. We also found a signaling pathway contributes to heat hypersensitivity caused by inflammation or nerve injuries.”

The study

Everything we do, including how we perceive the world around us, how we move our bodies, and how we feel sensations, is controlled by the brain. Neurons, which are cells that function as messengers to convey information between the brain and nervous system, are involved in the process. Through intricate circuits, the neurons communicate with the rest of the body.

The research team looked at neurons in the spinal cord and their role in thermal pain by analyzing mouse models and their response to heated plates. During this process, the team identified the activation of a “novel,” or newly discovered, class of spinal cord neurons (called ErbB4+) that process heat signals to the spinal cord.

They wanted to look further into whether these neurons specifically are responsible for thermal pain. There are several ways to test this, including destroying the ErbB4+ neurons.

The researchers expressed a toxin specifically targeting the ErbB4+ neurons. Once the neurons were destroyed, the response to heat pain was impaired. This demonstrated that ErbB4+ neurons are specifically tied to how thermal pain is sensed and, when destroyed, pain is not felt less.

The team also examined 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 the NRG1 signaling) are also involved in the sensation of thermal pain.

The findings

“Pain is a sensation we have all experienced. For most of us, pain is temporary,” said Lin Mei, professor and chair of the Department of Neurosciences at the School of Medicine and study corresponding author. “However, for patients with pathological pain, the pain experience is unending, with little hope for relief. Scientists have long believed it’s a result of dysfunctional neuronal 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 discoveries may go beyond the therapeutic treatment of pathological pain.

“Both NRG1 and ErbB4 are risk genes of many brain disorders including major depression and schizophrenia,” Mei said. “Further studies are warranted to show if the mechanism of heat pain and pathological pain also plays a role in different types of pain experienced by those who have brain disorders.”

Reference: “A novel spinal neuron connection for heat sensation” by Hongsheng Wang, Wenbing Chen, Zhaoqi Dong, Guanglin Xing, Wanpeng Cui, Lingling Yao, Wen-Jun Zou, Heath L. Robinson, Yaoyao Bian, Zhipeng Liu, Kai Zhao, Bin Luo, Nannan Gao, Hongsheng Zhang, Xiao Ren, Zheng Yu, James Meixiong, Wen-Cheng Xiong and Lin Mei, 11 May 2022, Neuron.
DOI: 10.1016/j.neuron.2022.04.021

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