Neuropathic pain represents a huge medical need affecting millions of individuals. The therapeutic approach remains a problem, as patients do not respond to traditional analgesics and even the efficacy of treatment with antiepileptics or antidepressants is poor. For these reason novel therapeutic strategies are urgently needed.
In neuropathic pain induced by nerve injury, damaged cells recruit circulating leukocytes and activate inflammatory cells, which produce several molecules, including chemokines.
Prokineticin 2 (PROK2) is a new chemokine that activating two G-protein coupled receptors, PKR1 and PKR2, localized in central and in peripheral nervous system, participates in the onset and progression of neuropathic pain. In different animal models of neuropathy, both PROK2 and PKRs result strongly up-regulated in the sciatic nerve, DRG and spinal cord and treatment with the PKRs antagonist PC1 reverses neuropathic pain restoring the PROK2/PKRs levels.
The project aims to understand if the prokineticin system plays a role not only in development but also in maintenance of neuropathic pain and also if this system may have a role in the regeneration of the nerve, after injury. For these reasons, we will evaluate in peripheral, spinal and supraspinal level, at several time points post-injury, the expression and distribution of PROK2/ PKRs, pro- and anti-inflammatory cytokines, the molecular phenotypes of infiltrating macrophages and of the glial cells. Moreover, in order to find out the role of the single prokineticin receptor in neuropathic pain, injury of the sciatic nerve will be induced in PKR1- and PKR2-KO mice and the time course of pain behavior will be evaluated up to complete recovery. At different time points after injury, we will evaluate the expression and distribution of PROK2/PKRs in peripheral and central nervous system as well as the single PKR-induced intracellular pathway that could contribute to neurodegeneration and/or nerve regeneration processes.
The interest of the study is aimed at the research of innovative therapeutic strategies for the treatment of persistent pain, particularly, of neuropathic nature.
Neuropathic pain is a condition of chronic and debilitating pain that profoundly affects the quality of life of the patient. The current available therapies are not conclusive and sometimes with serious side effects. In addition, chronic pain leads, in most cases, to the development of related pathologies such as motility and sensitivity deficits, disorders of the psychic sphere and depression and therefore, also, to an increase in the social cost. Finding new drugs for the treatment of neuropathic pain is important because of the strong impact it can have not only on public health but also on a socio-economic level.
So, it is evident the importance of deepening the study on the pathogenic mechanisms underlying neuropathic pain with the aim to discover new pharmacological targets.
A lot of evidence suggests that neuropathic pain following nerve damage is caused by a process of chronic inflammation. Cells damaged by nerve injury, induce a strong recruitment of circulating leukocytes to the site of lesion and activate macrophages, which produce several molecules, as chemokines [1] involved not only in pain enhancement, but also in the regulation of the regenerative response of the nervous system [2].
Prokineticin 2 (PROK2) is a chemokine that binding to prokineticin receptors, PKR1 and PKR2, modulates inflammatory and neuropathic pain [3].
In mice, sciatic nerve ligation induces the overexpression of PROK2 and its receptors in the injured nerve, in lumbar DRG neurons and in spinal cord neurons and astrocytes [4,5]. Therapeutic, sub-chronic treatment with the prokineticin receptor antagonist PC1 [6] impairs thermal hyperalgesia and tactile allodynia reducing PROK2 up-regulation, microgliosis and astrocytosis, and restoring the physiological balance between the pro-inflammatory and anti-inflammatory cytokines.
In this project, we propose to deepen our knowledge on the role played by the prokineticin system in neuropathic pain; particularly, we aim to understand the role of PROK2 and PKRs not only in development but also in maintaining neuropathic pain once it has been established. We will also evaluate if the prokineticin system is involved in the regulation of the regenerative responses of the nervous system that naturally occur after injury, and if PC1 ability to reduce pain is due to its capability to promote neuro-regeneration. Moreover, we wish to establish the role of the single PKR in neuropathic pain with the aim to understand which are the intracellular signaling mechanisms induced by the activation of each single PKR, that could contribute to neurodegeneration and/or nerve regeneration processes.
Understanding the role of the individual components of the prokineticin system in the onset and evolution of neuropathic pain would allow the identification of some crucial molecular signals that lead to the chronicity of the pain sensation.
This study, together with an important advancement in basic knowledge, lays the basis for the development of a new therapeutic approach with the identification of safer and more manageable drugs.
[1] Zhang et al. (2016). Journal of neurochemistry 136:837-850
[2] Bollaerts et al. (2017). Mediators of Inflammation 7, ID 9478542
[3] Negri and Ferrara (2018). Physiol. Rev. 98:1055-1082.
[4] Maftei et al. (2014). British journal of pharmacology 171:4850-4865
[5] Lattanzi et al. (2015). BioMed research international 2015:301292
[6] Balboni G. et al. (2008). J. Med. Chem. 51:7635-7639