The role of resolvins - a novel class of omega 3-derived lipid mediators - in chronic pain.
Lead Research Organisation:
University of Sheffield
Department Name: Clinical Dentistry
Abstract
An emerging line of investigation has suggested that a novel class of omega 3-derived, endogenous lipid mediators - resolvins - have a crucial role in the resolution of inflammation. Acute inflammatory responses are protective and usually culminate in the restoration of tissue homeostasis. However, if left uncontrolled, they fail to exert a protective function and become pathophysiological. In addition to its role in classic inflammatory diseases (eg arthritis), uncontrolled inflammation has been implicated in a growing range of age-related and other common chronic debilitating conditions including cardiovascular disease, neurodegenerative diseases, diabetes, obesity and chronic pain. Evidence now indicates that resolution of inflammation is an active process, which involves specialised molecules such as resolvins.
Recent work indicates that resolvins also have considerable potential to alleviate chronic pain. This condition shows increased prevalence with age, affecting patients across all clinical disciplines, however its pathogenesis is poorly understood. Pain represents a major area of unmet clinical need; 28 million people live with chronic pain in the UK and a recent Global Burden of Disease study highlights that burdens associated with chronic pain are increasing, and that chronic back pain is the greatest cause of years lived with disability.
Resolvins are derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and mediate their actions through specific G protein-coupled receptors (GPCR). Resolvin receptors have been identified in cells and tissues that are known to be significant in nociceptive processing and its modulation, including dorsal root ganglion (DRG) and spinal dorsal horn neurones, microglia and astrocytes.
Recent work has demonstrated upregulation of resolvin receptors in preclinical pain models and that administration of resolvins can reduce nociceptive behavioural responses in these models. We have shown that resolvin receptors are expressed at sites of nerve injury (linked with neuropathic pain) in man, and that microglial activation (linked to pain) correlates with resolvin receptor upregulation in a preclinical model. Other groups have investigated potential routes by which resolvins regulate activity in pain-sensing neurones. For example, it has been shown that D-resolvins can inhibit pain-related transient receptor potential channels in DRG neurones via a GPCR-mediated mechanism. However, the molecular basis of these inhibitory effects is not understood.
This collaborative project will use a multidisciplinary and translational approach employing the unique resources and expertise across the supervisory team to further understand how the effects of resolvins are mediated in peripheral neurones. The specific aims are to:
1) Characterise and quantify resolvin receptor expression in human tissues from patients with neuropathic pain (neuroma tissue) and inflammatory pain (dental pulp), correlating receptor expression with clinical pain history and altered sensitivity to peripheral stimuli.
2) Investigate the signalling cascades through which resolvins modify activity in pain-sensing neurones.
3) Determine the ability of resolvins to antagonise the excitatory effects of inflammatory mediators in pain-sensing neurones, and reduce pain-related behavioural responses in preclinical models.
These will be achieved using immunohistochemical, molecular biological (including RNA-seq and computational interrogation of publicly available datasets), electrophysiological (patch and voltage clamp), bioimaging (including live confocal and TIRF microscopy) and in vivo methods.
Recent work indicates that resolvins also have considerable potential to alleviate chronic pain. This condition shows increased prevalence with age, affecting patients across all clinical disciplines, however its pathogenesis is poorly understood. Pain represents a major area of unmet clinical need; 28 million people live with chronic pain in the UK and a recent Global Burden of Disease study highlights that burdens associated with chronic pain are increasing, and that chronic back pain is the greatest cause of years lived with disability.
Resolvins are derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and mediate their actions through specific G protein-coupled receptors (GPCR). Resolvin receptors have been identified in cells and tissues that are known to be significant in nociceptive processing and its modulation, including dorsal root ganglion (DRG) and spinal dorsal horn neurones, microglia and astrocytes.
Recent work has demonstrated upregulation of resolvin receptors in preclinical pain models and that administration of resolvins can reduce nociceptive behavioural responses in these models. We have shown that resolvin receptors are expressed at sites of nerve injury (linked with neuropathic pain) in man, and that microglial activation (linked to pain) correlates with resolvin receptor upregulation in a preclinical model. Other groups have investigated potential routes by which resolvins regulate activity in pain-sensing neurones. For example, it has been shown that D-resolvins can inhibit pain-related transient receptor potential channels in DRG neurones via a GPCR-mediated mechanism. However, the molecular basis of these inhibitory effects is not understood.
This collaborative project will use a multidisciplinary and translational approach employing the unique resources and expertise across the supervisory team to further understand how the effects of resolvins are mediated in peripheral neurones. The specific aims are to:
1) Characterise and quantify resolvin receptor expression in human tissues from patients with neuropathic pain (neuroma tissue) and inflammatory pain (dental pulp), correlating receptor expression with clinical pain history and altered sensitivity to peripheral stimuli.
2) Investigate the signalling cascades through which resolvins modify activity in pain-sensing neurones.
3) Determine the ability of resolvins to antagonise the excitatory effects of inflammatory mediators in pain-sensing neurones, and reduce pain-related behavioural responses in preclinical models.
These will be achieved using immunohistochemical, molecular biological (including RNA-seq and computational interrogation of publicly available datasets), electrophysiological (patch and voltage clamp), bioimaging (including live confocal and TIRF microscopy) and in vivo methods.
Organisations
People |
ORCID iD |
| Fiona Boissonade (Primary Supervisor) | |
| Natalie Wong (Student) |