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Neuropathic pain: biomarkers and druggable targets within the endogenous analgesia system

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Investigating the body’s natural pain relief system to develop new drugs

EU-funded scientists have found genetic and personality traits underlying difficult-to-treat neuropathic pain and conducted groundbreaking fundamental research that can lead to new drugs for this distressing condition.

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Neuropathic pain results from an alteration of the nervous system, unrelated to physical injury. “A viral infection, chemotherapy or an increase in glycaemia [in diabetics] can produce a lesion in the nerve leading to persistent, chronic neuropathic pain that is extremely difficult to manage,” says Prof. Rafael Maldonado, scientific coordinator of the EU-funded NeuroPain project and a professor in experimental and health sciences at Pompeu Fabra University in Barcelona, Spain. Few patients treated with currently-used drugs see any improvement. “They don’t have any relief from pain so we really need new treatments,” Prof. Maldonado explains. The huge NeuroPain project involved 11 universities, research institutions and companies over five years in investigating different aspects of neuropathic pain, leading to some 40 publications in academic journals. Among the breakthroughs, the project was able to identify personality traits and specific genes associated with neuropathic pain and develop two new compounds that show promise in treating such pain. Link with personality traits and genes The way people experience neuropathic pain depends on personality and some specific genes. “We investigated different traits – sociability, aggression and depression-like behaviour – and we identified that, surprisingly, the most well-correlated in the manifestation of neuropathic pain is sociability,” Prof. Maldonado explains. “With chronic pain we also have emotional components – anxiety, a depressive-like state, and our ability to make a decision is also impaired.” “We already knew there is a genetic basis to chronic pain and that, for instance, there are individuals that don’t feel pain,” Prof. Maldonado says. Studies were carried out in parallel in mice and in humans to identify genetic markers of different non-susceptive emotional, cognitive or behavioural manifestations of neuropathic pain. This involved a genome-wide approach used mainly in humans, analysing those with neuropathic pain compared to those not experiencing such pain; while in animals the researchers looked at candidate genes. “We suspected one particular gene could be involved in the particular response so we went directly to this group of genes to see which could be a biomarker,” says Prof. Maldonado. “Then we said let’s compare the biomarkers in the animals and in humans to see if there’s any particular biomarker across species,” Prof. Maldonado adds. This led to the identification of specific genetic biomarkers. Endogenous pain relief systems “Our bodies have molecules similar to morphine and molecules similar to cannabis, so the moment we feel pain we have a reaction which releases endogenous opioids and endogenous cannabinoids to minimise and avoid pain,” Prof. Maldonado explains. The project investigated the involvement of the two endogenous systems in neuronal pathways underlying neuropathic pain and used this fundamental research to develop novel compounds to treat neuropathic pain more efficiently. “We have identified a particular cannabinoid receptor and the precise mechanism by which it can modulate neuropathic pain. We identified very clearly the [molecular] pathway,” Prof. Maldonado says. “The interesting thing is that it is a receptor that can be activated by cannabis, but does not produce psychoactive effects,” Prof. Maldonado adds. This means it is a promising cannabinoid compound without the often serious side effects of existing cannabinoid drugs. With the project closed, Prof. Maldonado concludes: “We now have one novel compound acting on the opioid system at stage I clinical trials for treating neuropathic pain and we have identified a second [cannabinoid] compound where we already have proof of concept in humans.”

Keywords

NeuroPain, chronic pain, diabetes, nervous system, personality, genes, biomarkers, opioid, cannabinoid, drug development

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