Even healed nerve injuries often cause chronic pain and hypersensitivity to gentle touch. Scientists at the Institute of Pharmacology and the Institute of Anatomy and Cell Biology at the Medical Faculty of Heidelberg have now shown in animal experiments that miswiring of the pain receptors (nociceptors) leads to a form of so-called neuropathic pain that had not been investigated thus far. It occurs in the course of regeneration of nerve connections as the injury heals. The results were recently published in the scientific journal "Nature".  

Neuropathic pain, which an interdisciplinary research group investigated as part of the Collaborative Research Centers of the German Research Foundation (CRC) 1158 "From Nociception to Chronic Pain: Structure-function properties of neural pathways and their reorganization", occurs after traumatic injuries: In this case, not all fibers of a nerve supplying the skin, for example, are damaged; in addition, there are still intact fibers with preserved connections to the skin. "So far, only the reactions of these intact nerve fibers to external stimuli have been studied. They show sensitization leading to increased pain. In contrast, the status of the damaged nerves over the course of regenerative processes has hardly been investigated. Surprisingly, the research fields of regeneration and pain have been poorly linked so far. We performed research at the point of convergence of these two fields," explains senior author Professor Dr. Rohini Kuner, Director of the Department of Molecular Pharmacology at the Institute of Pharmacology and Spokesperson for CRC 1158.

Miswiring pain receptors are the cause of chronic pain

Chronic pain is divided into nociceptive and neuropathic pain. Nociceptive pain originates in tissue injury, neuropathic pain in damage to the nerve filaments themselves. Nerve trauma or bruising, in which injured and intact nerve fibers are intermingled, is particularly predisposed to the development of chronic neuropathic pain. The new results now show that the chronic pain does not result from the injury itself, but is due to incorrect restoration of nerve supply, known as reinnervation, over the course of regeneration.

The authors found that after nerve injury leads to loss of nerve fibers, tactile (touch-sensitive) nerve fibers that transmit touch stimuli to the spinal cord and brain do not reinnervate the affected area or do so only very slowly, hence initial leading to loss of sensation. In contrast, the pain-conducting fibers are able to reinnervate the injured area more quickly and are able to now take the place of the lost touch-sensitive nerves in the end organs (sensors) in the skin. As a result, a touch stimulus can now act like a pain stimulus - even a gentle caress or the feel of clothing on the skin can thereby cause pain. "The source of the pain is an incorrect wiring of tactile sensors and accordingly only occurs after some time has passed since the connection was made. This form of chronic pain is thus the direct result of the reinnervation of tactile sensors by pain-conducting fibers with the simultaneous absence of reinnervation of tactile nerve fibers. "This connection was previously completely unknown," says first author Dr. Vijayan Gangadharan.

"Our results answer the long-standing question of how complex neuropathic pain in patients occurs, for example, after nerve crush injuries. They build a bridge between the fields of regeneration and chronic pain and show the importance of neuronal maldevelopment during the healing process," adds Prof. Kuner. Currently, there is no treatment option to specifically relieve or prevent this form of chronic pain. In the future, the interdisciplinary team will therefore address the question of how the injured tactile fibers can be stimulated to regenerate so that the loss of balance between touch and painful sensations does not occur in the first place.

The new findings were only possible due to the explicitly interdisciplinary orientation of the project group. The teams led by Prof. Dr. Thomas Kuner from the Institute of Anatomy and Cell Biology at Heidelberg University and Prof. Dr. Björn Ommer from the Interdisciplinary Center for Scientific Computing at Heidelberg University, contributed modern and specially adapted imaging techniques as well as the corresponding machine learning algorithms to track and quantitatively analyze the healing of the nerve fibers over months. "With this joint project, we were once again able to demonstrate that interdisciplinary collaborations can contribute in a special way to answering fundamental, unsolved questions and lead to completely unexpected new insights," says Prof. Dr. Thomas Kuner. The interdisciplinary team also involved the research group of Prof. Dr. Stefan Lechner at the Pharmacological Institute with electrophysiological measurements and the research group of Prof. Moritz Helmstaedter at the Max Planck Institute for Brain Research in Frankfurt contributing to electron microscopic reconstruction of skin sensors and their miswiring.

Literature

Gangadharan, V., Zheng, H., Taberner, F.J. et al. Neuropathic pain caused by miswiring and abnormal end organ targeting. Nature (2022). https://doi.org/10.1038/s41586-022-04777-z

Contact

Prof. Dr. Rohini Kuner
Direktorin der Abteilung für Molekulare Pharmakologie
Pharmakologisches Institut der Medizinischen Fakultät Heidelberg
Tel.: 06221 54-16601
E-Mail: christl.gartner@pharma.uni-heidelberg.de