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Decomposition of pain into celltypes

Periodic Reporting for period 2 - PainCells (Decomposition of pain into celltypes)

Reporting period: 2019-02-01 to 2020-07-31

The importance of understanding the cellular and molecular mechanisms of chronic pain cannot be overestimated. If we understand how chronic pain arises and is maintained, it will open for rational analgesic strategies that can make a difference for the nearly 8% of the population which have so severe chronic pain that it negatively affects the daily life. The overall objective of this project is to better understand the cellular and molecular causes for chronic pain.
A general feature from our results is that each pain sensitive neuron type expresses channels and receptors predicting a unique response profile, often to multiple stimulus modalities such as chemical, thermal, and mechanical. Consistently, the different neuron types have variable contribution to the distinct sensory modalities and to chronic pain in animal models. As most of this work is performed in mouse as model organism, we have also determined the cellular basis for pain in non-human primate. This will allow the transfer of knowledge from research studies in the laboratory to humans in the clinic. The characterization of non-human primate neurons also allowed us to discover the neuronal type contributing to heritability to chronic pain in humans, which shows that pain is not one disorder, but several with different underlying molecular mechanisms.
Pain has historically been thought to arise from thin nerve endings located in the skin and tissues and organs of our body. We have discovered that the special cells, called terminal Schwann cells, that surround the pain-sensing nerve cells, appear to be involved in sensing pain and that these cells forms a previously unknown sensory organ in the skin. These terminal Schwann cells have an octopus-like shape with extensions that wrap around the ends of pain-sensing nerve cells that extend up into the outer layer of the skin. When artificially activating these cells, animal responses to heat, cold and pinprick pain is markedly increased. When artificially deactivating these cells, animals have a marked reduction in response to pinprick and pressure pain. Thus, we have discovered that pain-sensitive nerve cell terminals are not in fact always directly activated by a painful stimulus, but instead can be driven by associated terminal Schwann cells that build a web-like structure in the skin that works as a pain sensing organ. We have and will continue dissemination by means of publications in scientific journals, by attending and presenting at research meetings and by press releases and interviews with journalists.
We believe that our results already has gone beyond state of the art by discovering a new pain sensing organ and by providing new insights into the cellular basis, underlying mechanisms and heritability of pain. We hope that we can by the end of the project present a comprehensive and unbiased map of the cellular basis for acute and chronic pain.