Neuropathic pain is a type of chronic pain caused by damage to the nervous system caused mainly by metabolic diseases such as diabetes and arthritis, or by the side effects of some types of chemotherapy. It is estimated that it affects between 3% and 15% of the population, depending on the country, and there are no specific medications to treat it; those currently used were developed for other conditions, such as epilepsy and depression.
Now, after more than a decade of studies, a group of Brazilian scientists has discovered a mechanism associated with the development of this type of chronic pain. With this, a new phase of research opens, in which it will be possible to search for drugs capable of acting on this metabolic pathway and to trace a course of targeted therapies.
The study revealed the role of dendritic cells (part of the immune system) located in the membranes lining the central nervous system (the meninges) in the development of neuropathic pain by increasing the kynurenine metabolic pathway.
Responsible for the metabolism of tryptophan, an essential amino acid in the production of vitamin B3, this pathway plays an important role in many physiological processes in the human body, such as the regulation of the immune response. Other work has already linked increased kynurenine production with the development of symptoms of depression and psychiatric disorders, for example.
In the research, the scientists found that neuropathic pain fades when a kynurenine metabolic pathway initiated by an enzyme called indoleamine 2,3-dioxygenase (IDO1) is disrupted genetically or through drugs.
“It was a very long job because we always seek to go deeper to better understand the mechanisms behind it. The study required significant national and international collaboration, such as that of Professor Andrew Mellor [of Georgia Regents University], one of the best in the world leading experts in the field of IDO. With the results obtained, perspectives are opened for the development of new compounds to block this pathway. We believe that its inhibitors can play an important role in the control of this type of pain”, says Tiago Matar- Cunha, Professor at the Ribeirao Preto School of Medicine, University of São Paulo (FMRP-USP) and advisor to the study, whose first author was Alexander Magnin.
The research was published in La Revista de Investigación Clínica and received support from the São Paulo State Research Foundation (Fapesp) through a thematic project and from the Center for Research in Inflammatory Diseases (CRID) – Center for Research, Innovation and Publication (CEPID) of Fapesp based on the FMRP-USP. Researchers from the Ribeirao Preto School of Pharmaceutical Sciences (FCFRP-USP) and the University of Texas Health Sciences Center also participated.
According to Cunha, the discovery opened a new field of work, still unexplored, focused on analyzing the role of the meninges in the context of pain.
The involvement of the kynurenine pathway (whose formation depends on some enzymes, mainly IDO1) with pain has already been demonstrated. Because IDO1 is induced during pathological processes, particularly inflammatory processes, by proinflammatory cytokines, the researchers hypothesized that this neuroinflammation that occurs during the induction of neuropathic pain could increase IDO, raising the levels of these neurotoxic or neurostimulatory metabolites.
We have used many tools to show if these enzymes and products really have a role in this type of pain. We use rat models and show that animals deficient in these enzymes or their inhibitors can reduce neuropathic pain. From there we try to understand the mechanism”, details Matar Kinha.
The group used a model of neuropathic pain caused by damage to peripheral nerves, as well as activation of glial cells in the spinal cord (a type of cell in the central nervous system involved in immune responses). In the medulla, kynurenine was metabolized by astrocytes (neurons that support neurons) and there was also activation of glutamate receptors.
We have shown for the first time that when there is peripheral nerve damage, there is an infiltration of immune cells into the meninges covering the spinal cord and dorsal root ganglia, which produce mediators that would cause or maintain pain sensitivity. In this process, IDO1 and its metabolites are produced. We show that these metabolites come mainly from dendritic cells, which are located in the meninges, causing hypersensitivity and amplification of the glutamate pathway, whose receptors play an important role in chronic pain”, explains the researcher.
According to Cunha, although the study was done with models of pain caused by physical trauma (crushing or tearing of a ligament), the mechanism is similar in other neuropathic conditions, such as infectious diseases caused by viruses such as HIV.
The group of researchers is now seeking to establish alliances with pharmaceutical companies or other centers to collaborate in the study of molecules or drugs that can act on the mechanism and inhibit nerve pain.
Late last year, an article published in Nature Neuroscience by CRID scientists, including Mattar Cunha, and researchers from Harvard University (USA) showed that a non-lethal component of anthrax toxin has high analgesic potency. and can act directly on pain. including that nerve pain.
The anthrax toxin is derived from the bacterium Bacillus anthracis, which turns into spores when exposed to harsh environments that can cause skin blistering and respiratory problems in exposed people, resulting in death within hours. The research concluded that by binding to a receptor on these nerve cells, this piece of anthrax could be used as a vector capable of delivering other pain-relieving substances to nerve cells.