BJA/RCoA Project Grants

University of Cambridge

Title
How are neural mechanisms underpinning touch-evoked pain modulated by sensory expectation and cognition in individuals with Complex Regional Pain Syndrome

Amount
£54,272

Scientific Abstract
Chronic pain is a pressing challenge to the health system. Recent years have seen a shift from understanding chronic pain as a conscious percept determined by cognitions and pain-related expectations rather than a direct readout of a noxious input. Our aim is to test how (1) touch-evoked pain impacts information propagation reflecting pain predictions in patients with Complex Regional Pain Syndrome and (2) how cognitive demand might influence these pain predictions.

We will run a series of neurocognitive paradigms manipulating pain-related expectations while recording high-density EEG. First, we are planning to investigate how touch-evoked
pain alters information propagation in the cortical hierarchy underpinning neural pain predictions in CRPS. Second, we will disentangle the neural signature of pain predictions from neural adaptation to a regular painful stimulus. Third, we will investigate whether pain levels and predictive information flow between frontal brain areas and the pain-related cortical hierarchy will increase with cognitive demand. To test these hypotheses, we will obtain models of effective connectivity in the pain hierarchy underpinning neural markers of pain-related prediction errors. We envision that our study might inform neurocognitive aspects of pain therapy.

University of Leeds

Title
Transcriptional and functional changes underpinning acute and chronic mitochondrial dysfunction in human and murine malignant hyperthermia

Amount
£25,663

Scientific Abstract
Malignant hyperthermia (MH) is a potentially fatal hypermetabolic reaction affecting genetically susceptible individuals exposed to inhalational anaesthetics and suxamethonium. The primary defect causes calcium ion accumulation in the cytosol of skeletal muscle fibres. However, there is evidence to suggest that mitochondrial dysfunction may contribute to the variability in the clinical response and also in a variety of non-anaesthetic manifestations observed in carriers of RYR1 variants associated with MH. In preliminary experiments using permeabilized muscle fibres we have identified changes in mitochondrial function at baseline and after exposure to halothane in tissue from MH patients and from mouse models of MH. However, we need to undertake further work to determine if these changes are species specific and whether the changes observed in humans may be confounded by patient lifestyle. We will use muscle cells derived from MH mouse models and from humans carrying analogous RYR1 variants as those genetically engineered into the mice. We will support the relevance of our functional data by quantifying the expression of genes that are associated with mitochondrial function.

University of Leciester

Title
Use of novel fluorescent probes to examine MOP/NOP interaction: studies with Cebranopadol and AT-121 as mixed agonists

Amount
£59,829

Scientific Abstract
Opioid receptors are classified as classical naloxone sensitive MOP(mu:μ), DOP(delta:δ) and
KOP(kappa:κ) and the non-classical nociceptin/orphanin FQ (N/OFQ) receptor or NOP. All are capable of producing analgesia but there are differences related to species and routes of administration. Importantly there is growing evidence, now including the clinic, that these receptors interact with one another functionally and also structurally in the form of dimers.

The consequence is reduced side effect profile and of interest is reduced tolerance. Our hypothesis is that MOP and NOP receptors interact in a physical and functional way to (i) form a heterodimer and (ii) differentially affect cell signalling. We will use a series of novel probes; N/OFQATTO594 and DermorphinATTO488 to measure NOP and MOP receptor location/expression respectively in single and an in house made double NOP-MOP expression system; we have access to cebranopadol and AT-121 as novel mixed ligands. We will use the properties of the individual ligands in a FRET based assay to demonstrate dimer formation (physical). As both fluorescent analogues are agonists they will induce internalisation-this will be tracked as our functional readout. We will compare with more traditional radioligand based internalisation assays. We will look for differences in monomeric compared to dimeric receptors.