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The transition from acute to chronic pain

Prof. Dr. Rohini Kuner and fellow scientists from Heidelberg have shown that a protein that inhibits an enzyme produced by immune cells protects nerve cells from chronic hypersensitivity to neuropathic pain. Kuner is also the spokesperson of a new collaborative research centre in Heidelberg that is receiving funding from the German Research Foundation totalling over 12 million euros. The centre is seeking to find the reasons why acute pain becomes chronic and how this transition can be reversed or prevented.

Prof. Dr. Rohini Kuner, spokesperson of the collaborative research centre 1158 © Heidelberg University Hospital

Acute, sudden pain is normally a warning that something is wrong and that something has to be done to prevent greater tissue damage. The perception of pain is down to sensory neurons known as nociceptors which send signals to the spinal cord and brain in response to potentially damaging stimuli. The pain disappears when the damage is eliminated or cured. However, many chronic diseases are associated with long-lasting pain that, in contrast to nociceptive pain, can prevail even when the pain-causing stimuli are no longer present and the lesion has healed. This so-called neuropathic pain leads to changes in the nerves involved and to disrupted pain processing in the central nervous system.

How do the nerve fibres in the brain and spinal chord change as pain becomes chronic, or in other words, when nociceptive pain transitions into neuropathic pain? Are these changes the cause or result of chronic pain? How can the development of chronic pain be prevented or reversed? How do cognitive processes influence the development of chronic pain? These are the questions a new collaborative research centre (CRC) is seeking to answer. The CRC is receiving funding from the German Research Foundation (DFG) totalling 12.1 million euros for the next four years. It brings together 19 research projects, which are being carried out by researchers from the Medical Faculty at the University of Heidelberg, the Central Institute of Mental Health (ZI), the German Cancer Research Center (DKFZ), the European Molecular Biology Laboratory (EMBL), the Max Planck Institute for Medical Research and the University of Technology in Munich.

Prof. Dr. Rohini Kuner, director of the Institute of Pharmacology at the University of Heidelberg, is the spokesperson of the newly established CRC 1158 ("From nociception to chronic pain – structure-function properties of neural pathways and their reorganization"). Prof. Herta Flor, scientific director of the Institute of Neuropsychology and Clinical Psychology at the Central Institute of Mental Health (ZI) in Mannheim is the centre's deputy spokesperson.

From molecular biology to the patient and back

Lucas Vicuña, Institute of Pharmacology at the Heidelberg Medical Faculty © private

"While there have been major advances in the study of the molecular mechanisms of chronic pain in recent years, our knowledge of changes in the neuronal networks is still very sketchy," says Kuner who has been instrumental in elucidating the molecular mechanisms underlying neuropathic pain. In cooperation with colleagues from the DKFZ, Israel and the USA, the researchers from Heidelberg succeeded in showing that the protein SerpinA3N attenuates neuropathic pain. SerpinA3N inhibits leukocyte elastase, a proteolytic enzyme which is released by T lymphocytes after injury in response to inflammation.

"We were surprised to find that this enzyme plays such an important role in neuropathic pain," says Lucas Vicuña, a member of Kuner's team and first author of a paper that recently reported on these findings in the renowned journal Nature Medicine. The researchers showed that the enzyme was released by T lymphocytes that infiltrated the dorsal root ganglia in the spinal cord after nerve injury. "This mechanism was previously completely unknown," says Vicuña.

The researchers found that the elastase inhibitor SerpinA3N was upregulated in the dorsal root ganglia after nerve injury, thus reducing the perception of pain. Inhibition of SerpinA3N and T lymphocyte infiltration of the dorsal root ganglia have the potential to be used for developing new drugs against therapy-resistant chronic pain. Drugs targeting SerpinA3N and T lymphocyte infiltration are already under development, albeit for treating different indications.

The SerpinA3N experiments were conducted with wild-type and SerpinA3N-deficient mice. In an interview with the Pain Research Forum, Rohini Kuner explained that previously, her chronic pain research would initially involve looking for signalling pathways and then specifically investigating the pathways that could be connected with the pain. Nowadays, Kuner and her CRC 1158 colleagues take the totally opposite approach: they initially consider what might be happening in the patient, they design appropriate models, then they go on to substantiate their assumptions experimentally.

Causes of phantom pain

Prof. Dr. Herta Flor © ZI

Phantom pain is a fascinating form of chronic neuropathy. Phantom pain sensations are perceptions perceived by individuals as a result of limb loss. It was previously assumed that individuals who had their limbs removed by amputation only imagined the pain, without actually perceiving it. However, it is now known that the pain sensations are actually due to changes in the brain. Prof. Herta Flor and her colleague Dr. Jamila Andoh are carrying out a CRC 1158 project specifically focused on phantom limb sensations that result from altered neurological pathways in the brain.

Prof. Herta Flor explains phantom pain is caused by the reorganisation of a cerebral cortex region in which tactical and pain stimuli are processed. All body parts are represented in the somatosensory cortex that consists of distinct sensory areas which map to certain areas of the body, including the amputated limb. Rather than being static, this cortical map is modified by incoming nerve stimuli. This is referred to as cortical plasticity. Although a cortex region no longer receives nerve stimuli from a limb that has been amputated, the corresponding cortex region is not empty, but instead receives stimuli from neighbouring regions. The more the topography of the brain is reorganised, the greater is the sensation of phantom pain.

Stress and depression have been shown to increase the perception of phantom pain. It is known that chronic pain is influenced by cognitive processes that play an important role in anxiety and depression. The cortical plasticity that underlies the interaction between pain and depression is being studied in an SFB 1158-associated research project led by Prof. Andreas Meyer-Lindenberg, chairman of the ZI, and PD Dr. Walter Magerl, Centre for Biomedicine and Medical Technology at the University Medical Centre Mannheim.

Original publication:

Vicuña L, Strochlic DE, Latremoliere A, Bali KK Simonetti M, Husainie D, Prokosch S, Riva P, Griffin RS, Njoo C, Gehrig S, Mall MA, Arnold B, Devor M, Woolf CJ, Liberies SD, Costigan M, Kuner R: The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nature Medicine 21, 518-523 (2015).

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