The molecular mechanisms underlying the transition from acute to chronic pain! Insights from an unconventional Myosin protein – Myochronic

Transition from acute to chronic pain represents a major medical problem worldwide. Its impacts on health care costs and social lives of patients are dramatic. Chronic inflammatory, neuropathic or postoperative pain occurs as a consequence of aberrantly prolonged sensitization of pain pathways both in the peripheral and central nervous systems, causing either increased facilitation or loss of inhibition in pain-transmitting circuits. We know a great deal about the molecular and cellular mechanisms underlying both peripheral and central sensitization that control the onset of injury-induced acute pain. However, our knowledge on the molecular and cellular events that trigger the transition from acute to chronic pain is still limited. As a consequence, to date, there are no efficient strategies that can either prevent or treat chronic pain. During the course of my ERC-consolidating grant "Paineurons" we have made two major discoveries: (i) We identified an unconventional myosin protein whose loss-of-function (LoF) converted an acute and reversible inflammatory, neuropathic and postoperative pain into a long lasting and irreversible chronic pain. (ii) We uncovered a chemokine-like protein, TAFA4 that revealed to be a potent analgesic molecule against inflammatory and neuropathic pain (Delfini et al, Cell Reports, 2013) and www.painresearchforum.org/news/33428-tafa4-protein-calms-painful-touch).
We propose to use Myosin KO mice in combination with state-of-the-art RNA deep sequencing technology, behavioral pharmacology and proteomics to i) decipher the molecular mechanisms that trigger the transition from acute to chronic pain and ii) to design "à la carte" pharmacological therapies to prevent the establishment of chronic pain. We will use new mouse models to decipher the critical role of low threshold mechanoreceptors in chronic pain development.
This is a highly ambitious project that deals with major and fundamental biological questions that are of high interest to several world-class pain biologists. For the first two aims, we have strong preliminary data (see the core of the grant proposal) supporting the successful outcome of our proposal. Using the inflammatory pain paradigm we already identified different sets of differentially expressed (DE) genes at critical time points post-inflammation that will provide novel and unanticipated insights into the molecular players involved in the initiation and perpetuation of inflammation-induced chronic pain. Moreover, we used our mouse model in combination with aggressive behavioral pharmacology to show that TAFA4 (but not many other drugs routinely used in the clinic) strongly attenuated surgery-induced chronic pain in Myosin KO mice. For the last aim we already generated the Myosin cKO and launched the different crosses required to elucidate the role LTRMs-derived Myosin in the transition from acute to chronic pain.
Therefore, we have unique mouse models in which several induced acute and reversible pains are transformed into chronic pain, and a molecule which is a chemokine-like protein that is able to significantly prevent the development of chronic pain in Myosin KO mice. With these tools in hands we will definitely contribute to extending our understanding of the mechanisms responsible for the conversion of acute pain into chronic pain and we will also uncover the most appropriate pharmacological therapies that will prevent the onset and perpetuation of injury-induced chronic pain.
Such results will be of high relevance to pain biologists both at the basic science and at the clinical levels.