Neurophysiological and pharmacological assessment of endogenous pain modulation in the human spinal cord

Location: St Luke’s Campus

Department of Clinical and Biomedical Sciences, RILD Building, RD&E Hospital Wonford, Exeter

The University of Exeter’s Medical School/Department of Clinical and Biomedical Sciences is inviting applications for a PhD studentship fully-funded by the Faculty of Health and Life Sciences to commence on 25 September 2023 or as soon as possible thereafter. For eligible students the studentship will cover Home tuition fees plus an annual tax-free stipend of at least £17,668 for 3 years full-time, or pro rata for part-time study. 

Project Description:

Top-down endogenous inhibitory controls form part of a descending pain modulation system (DPMS). The DPMS is often dysfunctional in chronic pain patients and is therefore a target during the development of new centrally acting pain therapeutics. There is a growing body of evidence that suggests harnessing inhibitory activity within endogenous analgesic systems could provide a feasible route to precision manipulation of descending control circuits.

The application of a heterotopic noxious conditioning stimulus can be used to activate a spinally projecting monoaminergic inhibitory mechanism within the DPMS referred to diffuse noxious inhibitory control (DNIC) in animals, a process thought to be one of the underlying mechanisms of conditioned pain modulation (CPM) in humans. However, psychophysical measures of CPM have been shown to have close to poor test re-test reliability, which often limits the use of these paradigms in Go/No-go decision making during the development of new centrally acting pain therapeutics.

This PhD will explore the reliability of a semi-automated CPM paradigm using computer-controlled cuff pressure algometry alongside neurophysiological pain-related measures of brainstem and spinal cord activity. The use of these objective measures of the somatosensory system provides a means to measure another one of the hypothesised underpinning mechanisms of CPM (propriospinal mechanisms) as well as provide key insight into how spinal mechanisms of CPM converge in humans. These measures include 1) the RIII flexion reflex (i.e. a spinal nociceptive reflex) and 2) the cervical N13 component of somatosensory evoked potentials (N13 SEP; i.e. the post-synaptic response of wide dynamic range neurons in the dorsal horn). We will also assess the top-down influences of a cuff pressure conditioning stimulus on the R2 blink reflex, which is a polysynaptic circuit in the reticular formation of the pons and medulla in the brainstem. Gaining a deeper understanding of these brainstem and spinal cord mechanisms of endogenous pain modulation will provide important translational steps towards personalised and mechanism-driven pain relief for chronic pain patients. 

The CPM pathway is thought to have distinct monoaminergic pharmacology compared to other DPMS circuits, which have the potential to be harnessed during the development of new mechanism-driven pain therapies. However, there has been a lack of research into the use of new or existing therapeutics in healthy participants using reliable and objective assessments of the mechanisms of CPM. In this PhD we will therefore assess the influence of different monoaminergic pharmacology on CPM mechanisms. This will include the first ever cutting-edge study of the spinal analgesic mechanisms of psilocybin (i.e. a monoaminergic psychedelic) which has a strong potential as a future chronic pain therapy.

The aim of this PhD project is to first develop and assess the reliability of a novel neurophysiological assessment of spinal cord CPM mechanisms in healthy participants. The PhD will then explore the effects of 1) reboxetine (i.e. a noradrenaline re-uptake inhibitor) and 2) psilocybin on brainstem and spinal cord neurophysiological readouts of CPM. 

These objective measures of descending pain control have the potential to provide a cost-effective approach for screening efficacy of candidate pharmaceutical or non-pharmaceutical therapies before large-scale clinical trials in chronic pain patients. 

This award provides annual funding to cover Home tuition fees and a tax-free stipend. For students who pay Home tuition fees the award will cover the tuition fees in full, plus at least £17,668 per year tax-free stipend. Students who pay international tuition fees are eligible to apply, but should note that the award will only provide payment for part of the international tuition fee and no stipend. 

Studentship will be awarded on the basis of merit for 3 years of full-time study to commence on 25 September 2023. International applicants need to be aware that you will have to cover the cost of your student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.

The conditions for eligibility of home fees status are complex and you will need to seek advice if you have moved to or from the UK (or Republic of Ireland) within the past 3 years or have applied for settled status under the EU Settlement Scheme.

Entry requirements

Applicants for this studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in neuroscience, physiology, pharmacology, biomedical science or a related discipline.  

If English is not your first language you will need to meet the required level (Profile C) as per our guidance at https://www.exeter.ac.uk/pg-research/apply/english/

How to apply

In the application process you will be asked to upload several documents. 

• CV

• Letter of application (outlining your academic interests, prior research experience and reasons for wishing to undertake the project).

• Names of two referees familiar with your academic work. You are not required to obtain references yourself. We will request references directly from your referees if you are shortlisted.

• If you are not a national of a majority English-speaking country you will need to submit evidence of your proficiency in English.

The closing date for applications is midnight on Friday 31st March 2023.

Interviews will be held virtually / on the University of Exeter St Lukes Campus in the week commencing 17th April 2023. 

If you have any general enquiries about the application process please email pgrenquiries@exeter.ac.uk or phone +44 (0)1392 722730 (UK callers) +44 (0) 1392 723044 (International callers).

Project-specific queries should be directed to the main supervisor Dr Sam Hughes (S.H.Hughes@exeter.ac.uk)

For further information and to submit an application please visit - https://www.exeter.ac.uk/study/funding/award/?id=4681