BJA/RCoA PhD Studentship
The successful applicants for the BJA / RCoA PhD Studentship were:
Principal Applicant
Professor Helen Galley and Dr Barry McCormick
Consultant/Senior Lecturer in Anaesthesia & Pain Medicine, University of Edinburgh
Title
Antioxidant protection in mitochondria in chemotherapy-induced neuropathic pain
Amount
£67,716
Scientific Abstract
Severe chemotherapy-induced neuropathic pain is a challenging clinical problem, affecting up to a third of patients. Improved understanding of the underlying mechanisms is essential in order to develop effective and targeted treatments. Emerging evidence from chemotherapy-induced neuropathy models indicates that mitochondrial dysfunction as a result of oxidative stress, may play a key role. Antioxidants which accumulate within mitochondria protect against oxidative stress-induced damage better than non-targeted antioxidants in several disease models. Our pilot work has shown that in dorsal root ganglion cells, in vitro chemotherapy-induced mitochondrial damage can be prevented by mitochondrial antioxidants. Using our unique joint expertise in translational pain research and mitochondrial dysfunction, the proposed project will use a paclitaxel model of neuropathic pain to investigate the efficacy of mitochondrial targeted antioxidants on neuropathic pain. We will investigate markers of mitochondrial function, combined with detailed phenotyping of patients, to define potential predictive biomarkers of neuropathic pain. We hypothesize that in vivo these antioxidants may relieve neuropathic pain, with the opportunity of a rapid translation of a novel treatment to the clinic.
Final report from Dr B McCormick.pdf (467 KB)
Interim Report from Prof H Galley & Dr L Colvin (577 KB)
Please see the NIAA's position statement on the use of animals in medical research.
Principal Applicant
Professor David Lambert
Professor of Anaesthetic Pharmacology, University of Leicester
Title
Characterisation of fentanyl based bivalent opioids
Amount
£67,771
Scientific Abstract
Opioids produce tolerance leading to increased dosing and side-effects. Opioid receptors can interact and disruption of the DOP(ä;delta) receptor reduces tolerance to morphine acting at MOP(ì;mu). There is a move away from selective MOP-agonists in favour of non-selectivity or multiple targeting. This can be achieved in three ways; (i) using 2 drugs, (ii) using a non-selective bifunctional drug or (iii) designing a bivalent drug with two receptor selective pharmacophores. We have described a bifunctional MOP-agonist/DOP-antagonist and have applied the lessons learned to this new project utilizing some innovative chemistry. As part of a collaboration with chemists in the USA and Italy we will use several functionalised fentanyl (FF) molecules to which ligands selective for other opioid receptors can be added to create bivalent ligands. The FF molecules are already synthesised and coupling of one form to a prototype DOP-antagonist (H-Dmt-Tic-OH) is underway, creating a MOP-agonist/DOP-antagonist. We will characterise this and several other bivalent ligands in (i) receptor binding, (ii) [GTPãS binding and (iii) cAMP inhibition following acute and chronic treatment in single MOP and DOP and double MOP/DOP expression systems. Our hypothesis is that FF/DOP-antagonist bivalents will bind to and activate MOP and inhibit DOP. In double expression systems these molecules will produce less receptor desensitisation.
Final report from Prof D Lambert.pdf (114 KB)
