Targeting neuroinflammation to combat pathological pain in neurodegenerative diseases and chronic pain syndromes

Project Information

TOBeATPAIN

Grant agreement ID: 764860

DOI

10.3030/764860

Project closed

EC signature date 5 July 2018

Start date 1 August 2018

End date 31 July 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 2 870 359,20

EU contribution

€ 2 870 359,20

Coordinated by

KING'S COLLEGE LONDON
United Kingdom

Periodic Reporting for period 2 - TOBeATPAIN (Targeting neuroinflammation to combat pathological pain in neurodegenerative diseases and chronic pain syndromes)

Reporting period: 2020-08-01 to 2022-07-31

Summary of the context and overall objectives of the project

Chronic pain in musculoskeletal and neuropathic conditions remains a clinical issue as currently available painkillers are partially effective in some patients. In addition, with the increase of the ageing population, the management of pain is a significant public health concern. TOBeATPAIN ITN has addressed the need for novel and more effective treatments for chronic pain by defining neuroinflammatory mechanisms that regulate pain signalling in 1) neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease 2) musculoskeletal diseases such as Rheumatoid Arthritis and Fibromyalgia and 3) painful peripheral neuropathies like in Fabry disease and polyneuropathies. TOBeATPAIN approach has challenged the neuro-centric view that has dominated the pain research area and exploited the opportunity to control mechanisms of neuroinflammation as an innovative therapeutic avenue. With a focus on non-neuronal cells, the 11 Early Scientists Researchers (ESRs) have delineated novel pathways involved in neuron-immune communication and identified non-neuronal targets that offer opportunities for the treatment of chronic pain conditions. The exploitation of our data will eventually lead to improvement of the quality of life of Europeans and impact positively on the health economy of EU countries.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

TOBeATPAIN has investigated the underlying mechanisms of pathological pain in neurodegenerative diseases, musculoskeletal conditions, and peripheral neuropathies, with the aim delineate novel mechanisms and pathways. We have used animal models of Alzheimer’s disease (AD), Parkinson’s disease (PD), Fibromyalgia (FM), Rheumatoid Arthritis (RA), Fabry disease (FD), and peripheral nerve injury. We performed imaging studies in patients with RA and FM and performed analysis of inflammatory markers in biopsies of patients with neuropathic pain.
Overall, we obtained evidence for mechanistic roles played by non-neuronal cells, especially immune cells, in the establishment and development of pathological pain. Specifically, in a transgenic mouse of Alzheimer’s disease (AD), we observed smaller brain extracellular volume and more neuronal excitability. In AD mice, development of inflammatory arthritis pain is altered due the reduced sensitivity of the CNS resident immune cells (microglia) to noxious signalling conveyed by neurons from the joint. Still in AD mice the development of neuropathic pain is attenuated due immune cells that release analgesic factors that block nociceptive signalling at the source of pain in the injured nerve.
In a rat model of PD, we report the presence of neuroinflammation in pain related regions of both brain and spinal cord which is accompanied by a pain phenotype in a parkinsonian rat. Both neuroinflammation and pain can be decrease by the administration of anti-inflammatory drugs, suggesting a possible causal relationship.
In mouse model of FM, we provide evidence of altered glial activity in the dorsal root ganglia in the periphery that correlates with pain-like behaviour. Similarly, in models of RA we provide mechanistic evidence for a role of immune cells in the dorsal root ganglia in periphery but also a role of cytokines in the spinal cord where they sensitise neuronal activity and contribute to pain. Furthermore, in fibromyalgia (FM) patients we provide evidence that genetic variants of a marker of glial activation are related to endogenous pain modulation and that brain of RA patients display persistent changes in network interactions during evoked pain.
In a mouse model of Fabry disease (FD), we observed the development of neuroinflammation in the brain which may be causally involved in the development of pain and cognitive impairments. In neuropathic mice we detected that medical marijuana bioactive substances attenuate neuropathic pain and affect levels of cytokines in the dorsal root ganglia. Relevantly, in patients with peripheral neuropathy we have evidence for local inflammation in the peripheral nerve, which is involved in the sensitisation of primary afferents, and thus the development of pain.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

TOBeATPAIN focus on non-neuronal cell activity and neuroinflammation associated with pain in peripheral and central diseases has led to the delineation of novel pathways for non–neuronal cell-neuron communication and the identification of mediators involved in pathological pain signalling.
AD and PD: Our research may result in improved pain control of patients with AD that would reduce the impact that chronic pain has on psychiatric symptoms. Up to 80% of PD patients are affected by pain. We have identified an effective analgesic. However, the impact of this project on society will ultimately depend on the outcome of any subsequent clinical trials with analgesics borne out of the work conducted through TOBeATPAIN.
RA and FM: TOBeATPAIN has broaden our knowledge on immune mechanisms contributing to pain in RA and FM which may contribute to the development of new products and in the long-term have a more direct impact on our society.
FD and polyneuropathy: Furthermore, we have advanced our knowledge on Fabry disease and contribution of inflammation to painful peripheral neuropathies. We have begun the elucidation of the effect on neuropathic pain of active principle of medical marijuana bioactive substances. Our data when published will have a positive impact on the social acceptance of medical marijuana as a therapeutic agent. The quality of life of patients, who could benefit from the use of medical marijuana pharmaceuticals, could significantly increase.

TOBeATPAIN Dissemination by Jeiny Luna-Choconta

TOBeATPAIN Impact

TOBeATPAIN Project Logo designed by Andrea Ebersberger UKJ