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.
