The myelin barrier in neuropathic pain - barrier sealing and antinociception by specialized proresolving mediators

• Applicant: Professorin Dr. Heike Lydia Rittner
• Subject Area: Anaesthesiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433191715

Chronic pain is a major public health problem with epidemiological studies reporting about one fifth of the general population to be affected both in the USA and Europe. Especially challenging is treatment of neuropathic pain, which affects about 7 to 8% of the European population. Traumatic neuropathic pain after nerve injury, e.g. chronic constriction injury (CCI), is accompanied by blood nerve barrier (BNB) breakdown with loss of tight junction proteins (TJPs) in the perineurium or in endoneurial vessels. Less well examined is the myelin barrier (MB) sealing the paranode, mesaxon and Schmitt-Lantermann incisures. After nerve trauma, MB-TJPs, e.g. claudin-11-, 12, -19, are downregulated. Knockdown of claudin-12 or -19 in naïve animals also opens the MB and elicits mechanical hypersensitivity. Interestingly, MB-TJPs are not only reduced at the side of injury but also in the dorsal root ganglion proximal to the lesion. This points towards an affection of the whole myelinated primary afferent neurons. Signs of a neuropathic pain are found in the complex regional pain syndrome (CRPS) occurring after trauma of the extremities. CRPS is a rare disease with severe patients’ suffering and high long-term economic costs. Apart from neuropathic pain features, barrier disturbances with edema and decreased myelin density in the sural nerve are observed. Therefore, we want to examine the MB and the (dermal) myelinated fibers.During inflammation, in the first phase proinflammatory lipids like proalgesic prostaglandins are formed. This is followed by a phase of recovery by specialized proresolving mediators (SPM). SPMs are enzymatically converted from arachidonic acid (AA), eicosapentaenoic acid (EPA) and doxosahexanoic acid (DHA). They are known to upregulate TJPs in endo- or epithelial cells e.g. i the lung. In this proposal, we will explore in a translational approach how SPMs contribute to MB tightness and MB-TJPs in Schwann cells in neuropathic pain in rodents and patients with CRPS. Specifically, we will investigate the following hypotheses:Project A: Specific SPMs and their precursors are increased in the phase of MB sealing and recovery from CCI in male and female rats;Project B: SPMs treatment allows for resealing of the MB in male and female rats with CCI and ameliorates neuropathic pain while SPM-R knockdown reverses/prolongs this process;Project C: SPM treatment fosters MB formation in vitro in cultures of Schwann cells and neurons;Project D: CPRS-patient subtypes have MB breakdown with reduced expression of SPM-SPM-Rs and an unfavorable outcome.Using a multilevel, translational in vivo and in vitro approach we will decipher the role of the MB and SPMs in neuropathic pain and barrier sealing by SPMs. This will allow for the identification of new biomarkers and therapeutic targets.

• DFG Programme: Research Grants
• Major Instrumentation: Ganganalysegerät für Nager
• Instrumentation Group: 3490 Sonstige medizinische Registriergeräte und Zubehör
• Co-Investigators: Professor Dr. Robert Blum; Privatdozentin Dr. Kathrin Doppler; Professor Dr. Chi Wang Ip