Final Report Summary - PAIN PLASTICITY (The molecular and cellular basis of structural plasticity and reorganisation in chronic pain)
Chronic pain is a global health challenge. Although neural plasticity is recognized as a key pathophysiological cause for chronic pain, mechanisms are not well-understood. Although the notion that chronic pain-related plasticity can entail structural changes and reorganisation has been postulated, causal relationships and underlying mechanisms have not been studied adequately so far. One of our key goals in this project is to understand the nature, the functional relevance and the mechanistic basis of structural plasticity in the somatosensory nociceptive system. Throughout the funding period, we made several key observations on the molecular players that link disease-related functional changes in pain sensitivity and pathological hypersensitivity to structural changes in peripheral nerves as well as spinal synapses. We observed that spinal neurons undergo remarkable structural changes, particularly dynamic regulation of synaptic spine structure and density, that correlated temporally with the transition from acute to chronic inflammatory pain. Our work identified a novel genomic program which drives structural and functional changes in spinal neurons that is governed by calcium transients travelling into the nucleus of spinal neurons following nociceptive activity. Furthermore, we identified Kalirin-7 as a key convergence point of excitatory pathways in spinal neurons, which links potentiation of spinal neuron function to structural plasticity, i.e. increase in spine density, on the same neuron in the context of inflammatory pain. We observed that defects in regenerative mechanisms leading to aberrant connectivity of peripheral sensory afferents following nerve lesions accompany long-lasting deviations from normal pain sensitivity. Furthermore, we observed tremendous structural changes in peripheral nerves in the cancer-affected tissues, such as the skin and bone (metastases) in animal models as well as human cancer patients. Importantly, these changes were triggered by tumour-derived factors, such as growth factors from the vascular endothelial-derived growth factor family. In contrast, tumour-derived ligands from the Wnt family or lysophosphatidyl inositol markedly enhanced the sensitivity and function of nerves without inducing major structural changes. We developed novel, clinically-relevant models to test structural remodelling and functional plasticity in pancreatic adenoductal carcinoma, which is one of the most painful and lethal types of cancer.
A second goal of the ERC project is to delineate which cell types or multiple anatomical avenues in
the nociceptive system truly contribute to physiological pain and the pathological manifestations
of chronic pain. Our work identified certain non-neuronal cell types as key novel regulators of
pain chronicity. In particular, we observed that T-lymphocytes invade peripheral sensory ganglia and
directly cross-talk with sensory neurons via the secretion of leukocyte elastase, a protease that had
not been connected with neural function or pain before. We went on to directly test the therapeutic relevance of leukocyte elastase in pain caused by diverse disorders harbouring a neuropathic component, such as diabetic neuropathy, bone metastases and nerve injury. We also made major advances in understanding the contributions of developmentally active cues, such as semaphorins and their receptors, plexins, in inducing adult plasticity of sensory neurons during inflammatory pain in response to semaphorin release by immune cells and keratinocytes. Moreover, in the central nervous system, we unexpectedly observed that cross-talk between oligodendrocytes and spinal neurons is critical for maintaining axonal integrity, and a loss thereof can lead to aberrant pain. We also made significant contributions to our understanding of causal contributions of the somatosensory S1 cortex and the cingulate cortex towards acute and chronic pain using optogenetics and behavioral analyses in mice. We observed that while the S1 cortex is involved in acute pain sensitization, the mid-cingulate division of the cingulate cortex (MCC) plays a key role in the transition from acute to chronic nociceptive hypersensitivity. In contrast, the rostral/pregenual anterior cingulate cortex (rACC) was observed to only play a role in aversive responses that are linked to the affective component pain. Using diverse circuit-tracing approaches and optogenetics, we uncovered a previously unknown pathway from the MCC to the posterior insula which mediates nociceptive hypersensitivity. Finally, we addressed how these regions contribute to brain activity rhythms and observed that inhibitory GABAergic interneurons in the S1 cortex acutely enhance pain perception by increasing gamma oscillatory activity.
A second goal of the ERC project is to delineate which cell types or multiple anatomical avenues in
the nociceptive system truly contribute to physiological pain and the pathological manifestations
of chronic pain. Our work identified certain non-neuronal cell types as key novel regulators of
pain chronicity. In particular, we observed that T-lymphocytes invade peripheral sensory ganglia and
directly cross-talk with sensory neurons via the secretion of leukocyte elastase, a protease that had
not been connected with neural function or pain before. We went on to directly test the therapeutic relevance of leukocyte elastase in pain caused by diverse disorders harbouring a neuropathic component, such as diabetic neuropathy, bone metastases and nerve injury. We also made major advances in understanding the contributions of developmentally active cues, such as semaphorins and their receptors, plexins, in inducing adult plasticity of sensory neurons during inflammatory pain in response to semaphorin release by immune cells and keratinocytes. Moreover, in the central nervous system, we unexpectedly observed that cross-talk between oligodendrocytes and spinal neurons is critical for maintaining axonal integrity, and a loss thereof can lead to aberrant pain. We also made significant contributions to our understanding of causal contributions of the somatosensory S1 cortex and the cingulate cortex towards acute and chronic pain using optogenetics and behavioral analyses in mice. We observed that while the S1 cortex is involved in acute pain sensitization, the mid-cingulate division of the cingulate cortex (MCC) plays a key role in the transition from acute to chronic nociceptive hypersensitivity. In contrast, the rostral/pregenual anterior cingulate cortex (rACC) was observed to only play a role in aversive responses that are linked to the affective component pain. Using diverse circuit-tracing approaches and optogenetics, we uncovered a previously unknown pathway from the MCC to the posterior insula which mediates nociceptive hypersensitivity. Finally, we addressed how these regions contribute to brain activity rhythms and observed that inhibitory GABAergic interneurons in the S1 cortex acutely enhance pain perception by increasing gamma oscillatory activity.