Dr Rory Mitchell

Personal profile

• 2009 - present: Senior Lecturer, University of Edinburgh (Fellow of the British Pharmacological Society)
• 2004 - 2009: Wellcome Trust University Award
• 2004 - 2007: National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator
• 1999 - 2004: Medical Research Council (MRC) External Scientific Staff and Co-ordinator of MRC Membrane and Adapter Proteins Co-operative Group, University of Edinburgh
• 1981 - 1999: MRC Non-clinical Scientist (MRC Brain Metabolism Unit)
• 1979 - 1981: Parkinson’s Disease Society Fellow
• PhD in Molecular Pharmacology, MRC Neuropharmacology Unit
• BSc in Medical Biochemistry, University of Birmingham

Research Theme

• Synapses, Circuits and Behaviour
• Signalling, Homeostasis and Energy Balance   

Dr Rory Mitchell's research briefing

We are interested in fundamental mechanisms of signal transduction by receptors, especially unconventional pathways of G protein-independent signalling by G protein-coupled receptors.

This is applied to the research fields of psychotropic drug action and (in collaboration with Sue Fleetwood-Walker, CDBS) mechanisms of pain and analgesia.

New signalling pathways and in particular new ways of selectively accessing these with allosteric and biased ligands could hold great promise for fine-tuning therapeutic interventions to produce more selective beneficial actions while limiting side effects. 

We use a range of biochemical, pharmacological and molecular approaches to investigate these processes using in vitro cell models, ex vivo functional synaptic preparations as well as corresponding in vivo behavioural assessments. Studies on pain and analgesia focus on the receptor and signalling events underlying the processes of central sensitisation responsible for chronic hypersensitive pain states.

We discovered a novel endogenous analgesic system mediated by the TRPM8 ion channel and are currently working on the underlying peripheral and central mechanisms, clinical evaluation (in collaboration with Marie Fallon and Lesley Colvin), and a related drug-discovery programme.

Funding

• Merck KGaA

Team members

• Marta Mikolajczak (postdoctoral researcher)

Collaborations

International:

• Professor Chi-Wei Cheung and Dr Liting Sun (The University of Hong Kong, China), Professor Bert Joosten (University of Maastricht, The Netherlands). Neurostimulation and analgesia.
• Dr Christian Kirsten (Cancer Center, Kristiansand, Norway) and Dr Martin Michaelis (Preclinical Drug Discovery and Development, Merck KGaA, Darmstadt, Germany). The role of growth factor receptors in pain.

The University of Edinburgh:

• Professor Sue Fleetwood-Walker (CBDS). Mechanisms of pain and analgesia. Drug discovery – novel analgesics for neuropathic pain.
• Dr Don Mahad (Centre for Clinical Brain Sciences) and Dr Graham Campbell (CDBS). Role of Role of mitochondria function in pain/fatigue models of multiple sclerosis.
• Professor Philippa Saunders (Centre for Inflammation Research), Professor Andrew Horne and Dr Erin Greaves (MRC Centre for Reproductive Health). Endometriosis pain.
• Professor Juri Rappsilber (The Wellcome Trust Centre for Cell Biology). Molecular changes underlying lasting stress-induced neuronal hyper-responsiveness in pain pathways.
• Professor Marie Fallon (Cancer Research UK Edinburgh Centre) and Professor Ted Hupp (MRC Institute of Genetics & Molecular Medicine). New analgesic agents for control of cancer-induced chronic pain.
• Professor Stuart Ralston, Dr Simon Roberts (Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine) and Anna Törnqvist (Gothenburg University, Sweden). Molecular mediators and analgesia in osteoarthritis.
• Dr Dylan Clements (R(D)SVS/Roslin Institute). Mechanisms of osteoarthritis in dogs.

Publications

1. Sun, L, Tai, L, Qiu Q, Mitchell R, Fleetwood-Walker SM, Joosten EA, Cheung CW. (2017) Endocannabinoid activation of CB₁ receptors contributes to long-lasting reversal of neuropathic pain by repetitive spinal cord stimulation. Eur J Pain 21(5):804-814.

2. Greaves E, Horne AW, Jerina H, Mikolajczak M, Hilferty L, Mitchell R, Fleetwood-Walker SM, Saunders PT. (2017) EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis. Scientific Reports 7:44169.

3. Vinuela-Fernandez I, Sun L, Jerina H, Curtis J, Allchorne A, Gooding H, Rosie R, Holland P, Tas B, Mitchell R, Fleetwood-Walker SM. (2014) The TRPM8 channel forms a complex with the 5-HT_1B receptor and phospholipase D that amplifies its reversal of pain hypersensitivity. Neuropharmacology 79:136-151.

4. Sun L, Gooding HL, Brunton PJ, Russell JA, Mitchell R, Fleetwood-Walker SM. (2013) Phospholipase D-mediated hypersensitivity at central synapses is associated with abnormal behaviours and pain sensitivity in rats exposed to prenatal stress. Int J Biochem Cell Biol. 45(11):2706-12. 

5. Barclay Z, Dickson L, Robertson DN, Johnson MS, Holland PJ, Rosie R, Sun L, Fleetwood-Walker SM, Lutz EM, Mitchell R. (2011) 5-HT_2A receptor signaling through phospholipase D1 associated with its C-terminal tail. Biochemical Journal 436:651-60.  

6. Arbuckle MI, Komiyama NH, Delaney A, Coba M, Garry EM, Rosie R, Allchorne AJ, Forsyth LH, Bence M, Carlisle HJ, O'Dell TJ, Mitchell R, Fleetwood-Walker SM, Grant SG. (2010) The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol-3-kinase recruitment. EMBO Reports 11(6):473-8.

7. Proudfoot, CJW; Garry, EM;  Cottrell, DF; Rosie, R; Anderson, H; Robertson, DC; Fleetwood-Walker, SM & Mitchell, R. (2006) Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.

Current Biology 16: 1591-1605.

8. Johnson MS, Robertson DN, Holland PJ, Lutz EM, Mitchell R. (2006) Role of the conserved NPxxY motif of the 5-HT_2A receptor in determining selective interaction with isoforms of ADP-ribosylation factor (ARF). Cell Signal. 18(10):1793-800.

9. Garry, EM; Moss, A; O’Neill, F; Blakemore, J; Bowen, J; Husi, H; Mitchell, R;Grant, SGN & Fleetwood-Walker, SM. (2003) Lack of neuropathic pain behaviour and disruption of spinal NMDA receptor/CaM kinase II interaction in PSD-95 mutant mice. Current Biology 13 (4), 321-328.

10. Mitchell R, Robertson DN, Holland PJ, Collins D, Lutz EM, Johnson MS. (2003) ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor. J Biol Chem. 278(36):33818-30

Rory Mitchell publication list (PDF)

Information for students:

Willingness to discuss research projects with undergraduate and postgraduate students: YES - please click here