KFO 5001:  Peripheral mechanisms of pain and their resolution

• Subject Area: Medicine
• Term: since 2020
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586

Chronic pain is a significant global health problem, and understanding recovery mechanisms is essential for better prevention and treatment. The Clinical Research Unit “Peripheral mechanisms of pain and their resolution” (KFO5001 ResolvePAIN) was established to study why some patients recover from pain while others do not. By integrating clinical, preclinical, and basic sciences, the unit aims to uncover peripheral and systemic processes involved in pain persistence or resolution, along with their CNS control. Our research involving pain patients, animal models, and cellular systems has identified crucial factors for pain resolution. These include specific potassium channel subtypes that affect neuronal excitability, essential barrier proteins, the NGF-IL-7 axis, and sex-specific regulation of macrophage migration to the dorsal root ganglia (DRG). Additionally, resolution-related genes from Drosophila and human genes involved in pain resolution were identified through the exploratory projects Resolve2.0. Core units for standardizing blood and skin analyses and MR neurography for DRG imaging have been established, facilitating the study of differential effects in pain persistence and resolution. In the next four years, ResolvePAIN will verify these findings across various projects and species using advanced technologies. The research will focus on peripheral mechanisms in nerve endings, synaptic processes in the spinal cord, and CNS levels. Key areas include alterations in ion channel activities, local protein synthesis, transcriptional mechanisms, and synaptic plasticity. The unit will integrate expertise in cellular and molecular neurobiology, neurophysiology, imaging, and clinical trials. Five neuropathic diseases with transient pain will be the focus, using a collaborative approach. Projects will include studies on painful bortezomib-induced neuropathy (BIPN), analysing human biomaterials and patient-derived neuronal cells alongside animal models and in-vitro systems. In complex regional pain syndrome (CRPS), projects will validate blood immune signatures, extend imaging for a drug study, and initiate a psychological-social buffering intervention. Research on disorders with autoantibodies to contactin-associated protein 2 (Caspr2) will explore hyperexcitability induced by IgG versus immune complexes and their effects on the transcriptome. Two new disorders will be included, fibromyalgia syndrome (FMS) and chronic postsurgical pain (CPSP). Across diseases, we will investigate common resolution pathways. We will combine CNS-directed interventions with behavioural, systemic, and peripheral nociceptor-level readouts using newly acquired microneurography. Understanding the precise mechanisms of CNS-PNS interaction in pain resolution will help identify pathways to strengthen in at-risk patients, aiming to prevent chronic pain and promote pain resolution.

• DFG Programme: Clinical Research Units

Projects

• Brain stem circuits for pain regulation and resolution (Applicants Hein, Grit ;  Tovote, Philip )
• Clinical relevance of axonal NGF signalling for pain resolution after median laparotomy (Applicants Briese, Michael ;  Wagner, Nana-Maria )
• Coordination Funds (Applicant Rittner, Heike Lydia )
• Functional and metabolic investigation of nociceptive mechanisms underlying pain and pain resolution in Bortezomib‐induced polyneuropathy utilizing a patient‐derived in vitro model system (Applicants Oerter, Sabrina ;  Üçeyler, Nurcan )
• Methods core and training unit (Applicants Brack, Alexander ;  Pham, Mirko ;  Schlegel, Nicolas )
• Modelling barrier resealing of blood‐peripheral nerve and blood‐DRG barriers for pain resolution in nerve injury and complex regional pain syndrome (CRPS) (Applicants Krug, Susanne Marlen ;  Rittner, Heike Lydia ;  Schindehütte, Magnus )
• Molecular and cellular functions of Trk receptors in axonal induction and resolution of nociceptor excitability (Applicants Briese, Michael ;  Sendtner, Michael A. )
• Neuropathic pain induced by anti-Caspr2 autoantibodies: pathogenesis and resolution (Applicants Doppler, Kathrin ;  Villmann, Carmen )
• Neuropathic pain induced by anti Caspr2 autoantibodies: pathogenesis and resolution (Applicants Doppler, Kathrin ;  Villmann, Carmen )
• Physiological interaction of oxidized phospholipids, apolipoprotein A1, ABC transporter activity and cholesterol homeostasis in neuropathy and its resolution (Applicants Blum, Robert ;  Brack, Alexander )
• Presynaptic and peripheral plasticity of nociceptors in pain resolution (Applicants Kittel, Robert J. ;  Rittner, Heike Lydia )
• Resolution of neuropathies caused by bortezomib and its successor drugs (Applicants Einsele, Hermann ;  Kortüm, Martin ;  Sommer, Claudia )
• Single‐cell level phenotyping of multicellular dynamics in the DRG during pain resolution (Applicants Blum, Robert ;  Brack, Alexander )
• Social buffering and biomarkers in two primary chronic pain disorders (Applicants Hein, Grit ;  Namer, Barbara ;  Sommer, Claudia )
• Structural and molecular basis of pain and resolution in genetically determined neuropathies (Applicants Matthies, Cordula ;  Pham, Mirko )

• Spokesperson: Professorin Dr. Claudia Sommer
• Leader: Professorin Dr. Heike Lydia Rittner
• Project Heads: Professor Dr. Robert Blum; Professor Dr. Alexander Brack; Dr. Michael Briese; Privatdozentin Dr. Kathrin Doppler; Professor Dr. Hermann Einsele; Professorin Dr. Grit Hein; Professor Dr. Robert J. Kittel; Professor Dr. Martin Kortüm; Privatdozentin Dr. Susanne Marlen Krug; Professorin Dr. Barbara Namer; Dr. Sabrina Oerter; Professor Dr. Mirko Pham; Dr. Magnus Schindehütte; Professor Dr. Nicolas Schlegel; Professor Dr. Philip Tovote; Professorin Dr. Carmen Villmann; Professorin Dr. Nana-Maria Wagner; Professorin Dr. Nurcan Üçeyler