Projects per year
Tim Hales graduated with a BSc (Hons) in Physiology from King’s College London in 1986 and a PhD from the University of Dundee in 1990. He completed postdoctoral training in the Department of Anesthesiology, University of California in Los Angeles and in 1997 was appointed Assistant Professor at the George Washington University in Washington DC where he gained tenure in 2002. He became Professor in the Departments of Pharmacology and Anesthesiology & Critical Care Medicine and Director of Research in Anesthesiology at GWU in 2006.
Tim returned to Dundee in 2009 as Professor of Anaesthesia and non-clinical head of the Division of Neuroscience. He was elected Fellow of the Royal College of Anaesthetists in 2011 and was appointed Associate Dean for Research-Led Teaching in the School of Medicine in 2017. His research group studies the mechanisms of action of anaesthetics and opioid analgesics, drugs that modulate neuronal communication through ion channel modulation. The group’s work on metastatic colon cancer cells identified voltage-activated Na+ channels as potential targets for anticancer medications. Inhibition of these channels by local anaesthetics inhibits cell invasion.
Tim’s goal is to improve anaesthesia and analgesia by 1) educating future researchers and anaesthetists and 2) by identifying molecular targets responsible for the desirable and detrimental effects of anaesthetics and analgesics. His research has received support by grants from Tenovus Scotland, the National Science Foundation and the National Institutes of Health, USA and the National Institute of Academic Anaesthesia, UK.
Pain was an unavoidable consequence of injury, disease and infection before the advent of clinical anaesthesia. Now, thanks to skilled anaesthetists, pain-ameliorating analgesics and general anaesthetics (GAs), millions of people undergo surgery every year and most recover with relatively minor discomfort. While only a small minority of patients experience major negative consequences all anaesthetics have side effects. Most cause respiratory depression and some may cause neurodegeneration, a particular concern in the elderly. Analgesic agents also have severe side effects. Opioids such as morphine and fentanyl are commonly used to treat both perioperative and chronic pain; however their prolonged use leads to physical dependence and a loss of potency due to tolerance. Morphine can also cause hyperalgesia, a paradoxical increase in pain. There is a pressing need to develop better GAs and analgesics.
We are studying the mechanisms of action of opioids and GAs, drugs that influence neuronal excitability by binding to membrane proteins and thereby directly or indirectly regulating the activity of ion channels. By identifying the proteins responsible for their therapeutic and detrimental effects we hope to offer a strategy for improved safety and efficacy.
Opioid receptors (mu, delta and kappa) couple through G proteins to effectors, including K+ and Ca2+ channels. Morphine activates mu receptors thereby inhibiting Ca2+ channels, reducing excitatory transmission within the pain pathway. Prolonged morphine exposure leads to analgesic tolerance. Tolerance is attenuated in mice that lack beta-arrestin2, a protein that interacts with the mu receptor affecting its internalization and coupling it to signalling proteins including the tyrosine kinase, c-Src. We are testing the hypothesis that tolerance requires c-Src activity using electrophysiological recording and measurements of analgesia in mice.
Morphine induced hyperalgesia occurs in opioid receptor knock-out mice and is therefore independent of opioid receptor activation. We are using electrophysiological recording and behavioural assays to test the hypothesis that opioids directly modulate the activity of ion channels (e.g. the 5-HT3 receptor) and that these “off-target” actions contribute to their side effect profiles.
Research that began in the 1980’s in Dundee revealed that GAs, such as the induction agent propofol, enhance neuronal inhibition by the neurotransmitter gamma-aminobutyric acid (GABA) through a direct interaction with the GABAA receptor. GABA activates the GABAA receptor opening the integral Cl- channel and this activity is enhanced by GAs. The GABAA receptor is the primary target for induction agents. Since the 1980’s genes that encode 19 different GABAA receptor subunits have been cloned revealing considerable receptor heterogeneity. We identified the GABAA receptor epsilon subunit which reduces the enhancement of GABAA receptor function by GAs. The epsilon subunit may protect specific brain regions from inhibition by GAs. We are exploring the subtype specificity of GAs. Using chimeric constructs of the epsilon subunit and mutagenesis we are characterizing the nature of the GA interaction with the GABAA receptor.
Mutations in GABAA genes can profoundly affect the GA sensitivity of GABAA receptors. The artificial introduction of mutant receptors that are resistant to GA modulation makes mice resistant to immobilization by propofol validating GABAA receptors as the primary target of induction. We use homology modelling, mutagenesis and electrophysiological techniques to examine the relationship between structure and function of GABAA receptors and other related Cys-loop receptors. We recently demonstrated that mutations in individuals with epilepsy, which reduce GABA efficacy, enhance potentiation by propofol.
2009-present Level 3 and 4 Pharmacology and Neuroscience BSc and BMSc lectures in anaesthesia, anti-epileptics, drug dependence and opioids, University of Dundee
2009-present Supervision of BSc (Hons) and BMSc research projects.
2006-2009 Neurobiology 212: Lecturer - Introduction to neurobiology: freshman medical students. The George Washington University (GWU)
2005-2009 Pharmacology 170: Lecturer - Introduction to Pharmacology & Toxicology for undergraduate pharmacogenomics students. GWU
2004-2009 Pharmacology 202: Lecturer - Antiepileptic drugs: sophomore medical students. GWU
2000-2009 Pharmacology 502: Lecturer - Clinical use of drugs for 4th year medical students. GWU
2000-2009 Pharmacology 207: Lecturer - Pharmacology for GWU Physician Assistant students.
2006-2009 Mol. Medicine 280: Advanced neuropharmacology/neurophysiology for graduate students.
2005-2009 Biomed Sci 214: Lecturer - Cell Biology: receptors and ion channels. Graduate students.
1998-2009 Pharmacology 201: Lecturer - Pharmacology for sophomore medical students. Lectures on drugs of abuse, alcohol, general anesthetics, local anesthetics, anxiolytics and anticonvulsants. GWU
1998-2009 Pharmacology 201: Instructor - Autonomic pharmacology labs. GWU
1998-2006 Neuroscience 285: Course Director and lecturer - Neurophysiology for graduate students
1997- 2009 Pharmacology 205: Lecturer - Pharmacology lectures to graduate students. GWUMC.
1997-2009 Pharmacology 280: Lecturer - Pharmacology lectures to graduate students. GWUMC.
1997-2009 Biochemistry 280: Lecturer - Neurochemistry lectures to graduate students. GWUMC.
1997 HC66: Substance Abuse & the Brain. Lecturer - Honors Collegium. UCLA undergraduates.
1997 Neurobiology 101: Lecturer - Introduction to Molecular Neurobiology. UCLA undergraduates.
1995-1997 Cell & Tissue Neurobiology 209B: Lecturer - Neuronal electrophysiology. UCLA Access Graduate Students.
1994-1995 Neuroscience M202: Lecturer/Instructor - Receptors of Inhibitory Amino Acids. Lectures to 1st year UCLA IDP Neuroscience Graduate students.
1994 Neuroscience M211A . Lecturer – Neurodegeneration. UCLA Neuroscience Graduate Students.
1993-1996 Neuroscience 275A: Lecturer - Advanced Techniques in Neurobiology to 2nd year UCLA IDP Neuroscience Graduate students.
1992 Pharmacology 237A: Lecturer - Electrophysiology Lectures, 2nd year UCLA Pharmacology Graduate Dept. Pharmacology, UCLA.
1990-1992 Neuropharmacology Lecturer to Anesthesiology Residents. Dept. Anesthesiology, UCLA.
1986-1989 Instructor for the 2nd, 3rd and 4th year Neuropharmacology classes. Dept. Pharmacology, DundeeUniversity.
Expertise related to UN SDGs
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):
1/02/20 → 31/01/22
1/08/18 → 31/07/21
Neurosteroids: Modulation of Spinal Cord GABAa Receptors by Naturally Occuring Analgesics (Clinical PhD Programme: Stephen Humble)
Pharmacological and nutritional targeting of voltage-gated sodium channels in the treatment of cancersLopez-Charcas, O., Pukkanasut, P., Velu, S. E., Brackenbury, W. J., Hales, T. G., Besson, P., Gomora, J. C. & Roger, S., 23 Apr 2021, In: iScience. 24, 4, p. 102270 26 p., 102270.
Research output: Contribution to journal › Review article › peer-reviewOpen AccessFile6 Downloads (Pure)
TRV130 partial agonism and capacity to induce antinociceptive tolerance revealed through reducing available µ opioid receptor numberSingleton, S., Baptista-Hon, D. T., Edelsten, E., McCaughey, K. S., Camplisson, E. & Hales, T. G., Apr 2021, In: British Journal of Pharmacology. 178, 8, p. 1855-1868 14 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile4 Downloads (Pure)
Activation of μ-opioid receptors by MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) and its fluorinated derivativesBaptista-Hon, D. T., Smith, M., Singleton, S., Antonides, L. H., Daeid, N. N., McKenzie, C. & Hales, T. G., 9 Jul 2020, In: British Journal of Pharmacology. 177, 15, p. 3436-3448 13 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile3 Citations (Scopus)41 Downloads (Pure)
A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK BiobankMeng, W., Chan, B. W., Harris, C., Freidin, M. B., Hebert, H., Adams, M. J., Campbell, A., Hayward, C., Zheng, H., Zhang, X., Colvin, L., Hales, T., Palmer, C., Williams, F. M. K., McIntosh, A. M. & Smith, B. H., 15 Apr 2020, In: Human Molecular Genetics. 29, 8, p. 1396-1404 9 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile1 Citation (Scopus)16 Downloads (Pure)
Baptista-Hon, D., Hunter, W. & Hales, T., 15 Feb 2019, In: Journal of Biological Chemistry. 294, 7, p. 2375-2385 11 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile2 Citations (Scopus)48 Downloads (Pure)