Biology subjects

Chapman, V.

Publications and source records attributed to Chapman, V..

5 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↗

bioRxiv2022

No evidence for cognitive impairment in an experimental rat model of knee osteoarthritis and associated chronic pain

Although chronic pain states have been associated with impaired cognitive functions, including memory and cognitive flexibility, the cognitive effects of osteoarthritis (OA) pain remain to be clarified. The aim of this study was to measure cognitive function in the mono-iodoacetate (MIA) rat model of chronic OA-like knee pain. We used young adult male Lister hooded rats, which are well suited for cognitive testing. Rats received either a unilateral knee injection of MIA (3mg/50{micro}L) or saline as control. Joint pain at rest was assessed for up to 12 weeks using weight-bearing asymmetry, and referred pain at a distal site using determination of hindpaw withdrawal thresholds (PWT). The watermaze delayed-matching-to-place (DMP) test of rapid place learning, novel object recognition (NOR) memory assay and an operant response-shift and -reversal task were used to measure memory and behavioural flexibility. Open field locomotor activity, startle response, and prepulse inhibition (PPI) were also measured for comparison. MIA-injected rats showed markedly reduced weight-bearing on the injured limb, as well as pronounced cartilage damage and synovitis, but interestingly no changes in PWT. Rearing was reduced, but otherwise locomotor activity was normal and no changes in startle and PPI were detected. MIA-injected rats had intact watermaze DMP performance, suggesting no substantial change in hippocampal function, and there were no changes in NOR memory or performance on the operant task of behavioural flexibility. Our finding that OA-like pain does not alter hippocampal function, unlike other chronic pain conditions, is consistent with human neuroimaging findings.

neuroscience↗

bioRxiv2022

Complement receptor C5aR1 signaling in sensory neuron-associated macrophages drives neuropathic pain

Neuroimmune interactions across the pain pathway play a predominant role in the development of neuropathic pain. Previous reports demonstrated that complement driven effector systems including the C5a/C5aR1 axis contribute to these neuro-immune mechanisms. However, the cellular and molecular mechanisms underlying C5a/C5aR1 signaling-mediated neuropathic pain development remain ill-identified. Here we show that neuropathic pain following peripheral nerve injury was attenuated in C5aR1-deficient male and female mice as well as in wild type mice treated with a selective allosteric C5aR1 antagonist. Using two complementary cell-specific C5aR1 knockout mouse strains, we identified C5a/C5aR1 driven-activation of sensory neuron-associated macrophages (sNAMs) located in the sensory ganglia as the key site of peripheral nerve injury-induced neuropathic pain, whereas activation of macrophages of the local of peripheral nerve injury was not involved. Mechanistically, we uncovered IL-1b the main mediator of pain hypersensitivity in response to C5aR1 signaling in sNAMs. Our findings highlight a crucial role of C5a/C5aR1 axis activation in sNAMs for the development of neuropathic pain and identify this pathway as a promising novel target for neuropathic pain therapy.

pharmacology and toxicology↗

bioRxiv2020

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia

Chronic pain states such as osteoarthritis (OA) are often associated with negative affect, including anxiety and depression. This is, in turn, associated with greater opioid analgesic use, potentially contributing to current and future opioid crises. We utilise an animal model to investigate the neurobiological mechanisms underlying increased opioid use associated with high anxiety and chronic pain. Combining a genetic model of negative affect, the Wistar Kyoto (WKY) rat, and intra-articular injection of monosodium iodoacetate (MIA; 1mg), our model of high anxiety and augmented OA-like pain behaviour mirrors the clinical problem. Effects of morphine (0.5-6mg.kg-1) on pain behaviour and spinal nociceptive neuronal activity were determined in WKY rats, and normo-anxiety Wistar rats, 3 weeks after MIA injection. WKY rats developed augmented OA-like pain, and had blunted inhibitory responses to morphine, when compared to Wistar rats. Potential alterations in endogenous opioid function were probed via systemic blockade of opioid receptors with naloxone (0.1-1mg.kg-1), quantification of circulating levels of {beta}-endorphin, and determination of spinal expression of the mu-opioid receptor (MOR). These studies revealed increased opioidergic tone, and increased spinal desensitization of MORs via the master phosphorylation site at serine residue 375, in this model. We demonstrate attenuated MOR function in the absence of previous exogenous opioid ligand exposure in our model of high anxiety and OA-like pain, which may account for reduced analgesic effect of morphine and provide a potential explanation for increased opioid analgesic intake in high anxiety chronic pain patients. Significance StatementChronic pain affects large numbers of people, and pain management often relies on poorly effective opioid analgesics, the iatrogenic effects of which are increasingly recognised. The endogenous opioid system - the target for exogenous opioid analgesics - plays key roles in emotional affective states and pain control, but the complex interplay between anxiety, chronic pain, and endogenous opioid system function is challenging to study in people. Here, we have addressed this using a clinically-relevant experimental model. Anxiety-like behaviour was associated with increased chronic arthritis-like pain behaviour, altered opioid receptor function, and reduced efficacy of opioid analgesics. We provide new evidence, which may explain why chronic pain patients with comorbid high anxiety have higher opioid analgesic use.

neuroscience↗

bioRxiv2020

Variation in the expression of a transmembrane protein influences cell growth in Arabidopsis thaliana petals by altering auxin availability.

BackgroundThe same species of plant can exhibit highly diverse sizes and shapes of organs that are genetically determined. Defining genetic variation underlying this morphological diversity is an important objective in evolutionary studies and it also helps identify the functions of genes influencing plant growth and development. Extensive screens of mutagenised Arabidopsis populations have identified multiple genes and mechanisms affecting organ size and shape, but relatively few studies have exploited the rich diversity of natural populations to identify genes involved in growth control. ResultsWe screened a relatively well characterised collection of Arabidopsis thaliana ecotypes for variation in petal size. Association analyses identified sequence and gene expression variation on chromosome 4 that made a substantial contribution to differences in petal area. Variation in expression of At4g16850 (named as KSK), encoding a hypothetical protein, had a substantial role on variation in organ size by influencing cell size. Over-expression of KSK led to larger petals with larger cells and promoted the formation of stamenoid features. The expression of auxin-responsive genes known to limit cell growth was reduced in response to KSK over-expression. ANT expression was also reduced in KSK over-expression lines, consistent with altered floral identities. Auxin availability was reduced in KSK over-expressing cells, consistent with changes in auxin-responsive gene expression. KSK may therefore influence auxin availability during petal development. ConclusionsUnderstanding how genetic variation influences plant growth is important for both evolutionary and mechanistic studies. We used natural populations of Arabidopsis thaliana to identify sequence variation in a promoter region of Arabidopsis ecotypes that mediated differences in the expression of a previously uncharacterised membrane protein. This variation contributed to altered auxin availability and cell size during petal growth.

plant biology↗