PhD Studentship: Neurophysiological and Pharmacological Assessment of Endogenous Pain Modulation in the Human Spinal Cord

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.

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