PhD Studentship: The role of resolvins in the regulation of nociceptive processing

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 affects 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 this condition are increasing.

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. 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 project will use in vitro techniques, preclinical models and human tissues to further understand how the effects of resolvins are mediated in peripheral neurones.

The specific aims are to:

1. Caracterise 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 mechanisms through which resolvins modify activity in pain-sensing neurones.
3. Determine their ability to reduce pain-related behavioural changes in preclinical models of neuropathic pain.

These will be achieved using immunohistochemistry, molecular biology (including RNA-seq and computational interrogation of publicly available datasets), in vitro imaging and behavioural studies.

Funding Notes

The Faculty Scholarships for Medicine, Dentistry & Health cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.