The NGF System and its interplay with endocannabinoid signalling, from peripheral sensory terminals to the brain: new targets for the development of next generation drugs for neuropathic pain

Among different forms of chronic pain (CP), neuropathic pain (NP) is a form of neurogenic pain arising from nerve injury in the peripheral or central nervous system, while osteoarthritis (OA) is a progressive degeneration of cartilage of joints and is characterized by inflammation and pain. So far, there are no effective and specific treatments for these disabling disease and current treatments suffer from serious unwanted side-effects.

The Nerve Growth Factor (NGF) system is emerging as a key player in the onset and progression of NP and OA. The PAINCAGE project will systematically investigate the interactions within the NGF system itself and with the other players involved, peripherally and centrally, in the NP transmission and perception, such as the endocannabinoid (EC) system, focussing at different levels of pain transmission and perception, from peripheral sensory terminals to the brain.

Blocking the NGF signaling system is therefore a rational and thoroughly validated approach to pain therapy. Extensive evidence for potent analgesic efficacy of antiNGF mAbs has been obtained in preclinical models and in clinical trials, showing remarkable analgesic efficacy and creating great expectations for this new class of analgesic compounds. However, potential safety concerns related to off-target side effects have been raised and recently the FDA called for more preclinical research.

To fully exploit the huge therapeutic potential of NGF system, we have built a consortium of leading researchers in the NGF, EC and pain scientific arena. In this EU funded three years project the above consortium will investigate new strategies for the treatment of different NP forms, based on the NGF system and its interplay with EC signalling, focussing at different levels of the pain transmission and perception systems.

The project results will provide solid, mechanism-based grounds for the development of already identified second-generation therapeutics, based on the “NGF target” system, as well as for the identification and validation of new druggable targets emerging from the elucidated mechanisms. It will also identify biomarkers for NP, validated in animal models and clinical samples, that could result in future clinical benefits, for the stratification of patients suffering from different neuropathies and their treatment.

The project will contribute to the understanding and controlling NP mechanisms, with an interdisciplinary approach, leading to the development of next-generation NGF targeting drugs.