Biology subjects

Pope, R.

Publications and source records attributed to Pope, R..

3 recordsLinked to original sources

bioRxiv2025

Conserved Axonal Transcriptome Dynamics Underlie PGE2-Induced Sensitisation and Identify Tnfrsf12a/Fn14 as a Regulator of Neuronal Excitability in DRG Neurons

Chronic pain arises when dorsal root ganglion (DRG) neurons become sensitised to noxious inputs, a process driven by inflammatory mediators such as prostaglandin E2 (PGE2). Local translation of axonal mRNAs is a key regulator of nociceptor plasticity, yet how axonal transcriptome dynamics contribute to inflammatory sensitisation remains unclear. Using compartmentalised culture systems and RNA-sequencing, we defined axonal and somatic transcriptomes in embryonic (E16.5) and adult (W8) DRG neurons and assessed their remodelling after PGE2 exposure. We identify a conserved core axonal transcriptome spanning embryonic to adult stages, prominently enriched for ribosomal and mitochondrial functions, consistent with sustained translational and metabolic demands. PGE2 elicited compartment-specific reprogramming: pathways related to sensory processing and pain were upregulated in axons but downregulated in somata. Functionally, prolonged axonal PGE2 exposure enhanced capsaicin-evoked Ca{superscript 2} responses and drove retrograde sensitisation of neuronal somata. Integrating transcriptomics with functional assays, we pinpointed Tnfrsf12a (Fn14), a cytokine receptor linked to regeneration and neuropathic pain, as a PGE2-induced axonal mRNA. Crucially, local axonal knockdown of Tnfrsf12a significantly reduced neuronal excitability, providing proof-of-concept that axonally enriched transcripts can be targeted to modulate sensitisation. These findings position conserved axonal transcriptome programmes as drivers of peripheral sensitisation and establish Tnfrsf12a as a therapeutic candidate for inflammatory pain.

neuroscience↗

bioRxiv2020

Individual and combined effects of Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) on striato-cortical connectivity in the human brain

Cannabidiol (CBD) and {Delta}9-tetrahydrocannabinol (THC) are two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have somewhat opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Across two placebo-controlled, double-blind studies, we examine the effects of THC, CBD, and THC+CBD on the functional connectivity of striatal sub-divisions (associative, limbic, and sensorimotor) using resting-state functional Magnetic Resonance Imaging (fMRI) and seed-based functional connectivity analyses. Study 1 (N=17; inhaled 8mg THC, 8mg THC+10mg CBD, placebo) showed strong disruptive effects of both THC and THC+CBD conditions on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum, which was alleviated in the THC+CBD condition such that it did not differ from placebo. In Study 2 (N=23, oral 600mg CBD, placebo) CBD increased connectivity in the associative network, but relatively minor decreases/disruptions were found in the limbic and sensorimotor. In conclusion, THC strongly disrupts striato-cortical networks, and this effect is selectively mitigated in the limbic striatum when co-administered with CBD. When administered alone, 600mg oral CBD has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis related disorders, and the development of cannabinoid therapeutics.

neuroscience↗

bioRxiv2018

Predictors of emergency department attendance following NHS 111 calls for children and young people: analysis of linked data

ObjectivesTo assess whether clinical input during calls to the NHS 111 telephone-based advice service is associated with lower rates of subsequent emergency department attendance and hospital admission.\n\nDesignAlthough NHS 111 largely employs non-clinical call handling staff to triage calls using computerised clinical decision support software, some support is available from clinical supervisors, and additionally some calls are referred to out-of-hours General Practitioners (GP). We used linked data sets to examine GP and secondary care activity following calls to NHS 111, adjusting for the patient characteristics, signs and symptoms recorded during the NHS 111 call.\n\nSettingOut-of-hours care in three areas of North West London that have an integrated approach to delivering NHS 111 and out-of-hours GP care.\n\nParticipantsNHS 111 calls for children and young people aged 15 years or under. We excluded calls that were diverted to the emergency ( 999) service or where patients were advised to go to an emergency department. This left callers who were either referred to a GP or advised to manage their health needs at home.\n\nPrimary and secondary outcome measuresThe percentage of callers attending any emergency departments, major emergency department, or minor injury unit within ten hours of the NHS 111 call, and the percentage admitted to hospital following visits to emergency departments.\n\nResultsOf the 10,356 callers, 2,898 (28.0%) were advised by NHS 111 to manage their health needs at home, with an appointment with an out-of-hours GP made for the remaining 7,458 (72.0%). 14.9% (432/2,898) of the callers who were advised by NHS 111 to manage their health needs at home attended an emergency department with ten hours, compared with 16% (1,207/7,458) of callers who had an out-of-hours appointment with an out-of-hours GP. After adjusting for patient characteristics, GP out-of-hours appointment was associated with lower rates of emergency department attendance (adjusted odds ratio, 0.86, 95% CI, 0.75-0.99),). When we subset emergency department types, a GP out-of-hours appointment was associated with lower rates of minor injury unit attendance (adjusted odds ratio, 0.32, 95% CI, 0.23 - 0.44) but not major emergency department attendance (adjusted odds ratio 1.06, 95% CI 0.90-1.24). There was no association with hospital admission. Review by an NHS 111 clinical supervisor was associated with fewer emergency department attendances (adjusted OR 0.77, 95% CI, 0.62-0.97).\n\nConclusionsClinical input during or following out-of-hours calls to NHS 111 was associated with lower rates of emergency department utilisation for children and young people, though the reduction may be concentrated in lower intensity care settings. Thus, there may be potential to reduce the use of emergency care by providing access to clinical advice or out-of-hour services in other settings through the NHS 111 telephone service.

epidemiology↗