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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

All current therapeutic options for NP and OA relief (NSAIDs, opioids, antidepressants and anti-convulsants) are unsatisfactory and commonly associated with severe unwanted side-effects. Only 40% of patients achieve partial relief and some of them become resistant to drugs (Dworkin et al, 2007).

If Neuropathic Pain (NP) is inadequately treated, associated symptoms can include chronic anxiety, fear, depression, sleeplessness and impaired social interactions. In this respect, very little is known on the emotional-affective and cognitive components of NP. In fact, NP is more complex than simple nociception. Individual’s genotypes, previous learning processes, environmental and socioeconomic resources, cognitive, emotional and behavioral factors, and co-existent physical diseases interact to mediate and modulate the experience of pain. Thus, improving patients’ treatment will require that all contributing factors are considered. For all the above reasons, there is an urgent need for more insights in the NP mechanisms from periphery to the brain, to obtain more effective and safer analgesic drugs.


Objectives

The EU funded three years project PAINCAGE will pursue the following specific S&T objectives:

  • To understand the cognitive emotional and behavioral components of pain;
  • To identify, develop and validate new specific therapeutic targets for Neuropathic Pain and Osteoarthritis,
  • To identify neuronal and glial circuitries and processes modulating nociception and endogenous analgesia;
  • To develop a pipeline of second generation NGF-system-based compounds, for an improved control of Neuropathic Pain and Osteoarthritis;
  • To identify new markers from human samples for patient stratification;
  • To improve safety profile of pharmacological approaches for Neuropathic Pain and Osteoarthritis, currently undergoing clinical testing and targeting the NGF system.

Methodology

To achieve its aims, PAINCAGE will investigate

  1. the role of the individual components of the NGF and endocannabinoid systems in the regulation of Neuropathic Pain, including neuronal, inflammatory and neurotrophic mechanisms,
  2. the clinically proven or potential liabilities and safety concerns of targeting the NGF system for the treatment of Neuropathic Pain,
  3. the regulation of new targets by the NGF system and related signaling,
  4. the relationship between endocannabinoid and NGF signaling in healthy subjects and Neuropathic Pain patients.

More on Methodology.


Impact

Compared to current pain research, the PAINCAGE Project is the first to tackle the Neuropathic Pain (NP) and Osteoarthritis (OA) problem focusing on the proNGF/NGF-mediated signaling through their interaction with TrkA/p75NTR and sortilin receptors and on the interaction of the NGF system with another crucial player in the pain mechanisms, the Endocannabinoid system. A distinctive and innovative aspect of the PAINCAGE proposal is the analysis at different levels of the pain processing and perception cascade, from periphery to the central cortical areas, thereby studying also the emotional and cognitive aspects involved in NP. From a pharmacological perspective, these studies will lay solid foundations for the development of next-generation drugs targeting the NGF system and for new therapeutical designs, such as the association of (phyto/endo-) cannabinoidand NGF-derived drugs. From a clinical perspective, these studies will allow the identification and validation of new biomarkers to devise ad hoc, patient-selective treatments.

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