Biology subjects

Hilton, H.

Publications and source records attributed to Hilton, H..

3 recordsLinked to original sources

bioRxiv2024

Activation of the proton-sensing GPCR, GPR65 on fibroblast-like synoviocytes contributes to inflammatory joint pain.

Inflammation is associated with localised acidosis, however, attributing physiological and pathological roles to proton-sensitive receptors is challenging due to their diversity and widespread expression. Here, agonists of the proton-sensing GPCR, GPR65, were systematically characterised. The synthetic agonist BTB09089 (BTB) recapitulated many proton-induced signalling events and demonstrated selectivity for GPR65. BTB was used to show that GPR65 activation on fibroblast-like synoviocytes (FLS), cells that line synovial joints, results in the secretion of pro-inflammatory mediators capable of recruiting immune cells and sensitising sensory neurons. Intra-articular injection of BTB resulted in GPR65-dependent sensitisation of knee-innervating neurons and nocifensive behaviours in mice. Stimulation of GPR65 on human FLS also triggered the release of inflammatory mediators and synovial fluid samples from human osteoarthritis patients were shown to activate GPR65. These results suggest a role of GPR65 in mediating cell-cell interactions that drive inflammatory joint pain in both mice and humans.

neuroscience↗

bioRxiv2023

Digging deeper into pain - an ethological behavior assay correlating well-being in mice with human pain experience.

The pressing need for safer, more efficacious analgesics is felt worldwide. Pre-clinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays which measure their responses to noxious stimuli. The disconnect between how pain is tested in laboratory animals and how it is experienced by humans may in part explain the shortcomings of current pain medications and highlights a need for refinement. Here, we survey human chronic pain patients who assert that everyday aspects of life, such as cleaning and leaving the house, are affected by their on-going level of pain. Accordingly, we test the impact of painful conditions on an ethological behavior of mice, digging. Stable digging behavior was observed over time in naive mice of both sexes. By contrast, deficits in digging were seen following acute knee inflammation. The analgesia conferred by meloxicam and gabapentin was compared in the monosodium iodoacetate knee osteoarthritis model, meloxicam more effectively ameliorating digging deficits, in line with human patients finding meloxicam more effective. Lastly, in a visceral pain model, the decrease in digging behavior correlated with the extent of disease. Ultimately, we make a case for adopting ethological assays, such as digging, in studies of pain in laboratory animals, which we believe to be more representative of the human experience of pain and thus valuable in assessing clinical potential of novel analgesics in animals.

neuroscience↗

bioRxiv2023

Inhibition of sensory neuron driven acute, inflammatory, and neuropathic pain using a humanised chemogenetic system

Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM4-GlyR is a modular system based on the human 7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically-approved drug, varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally-mediated expression of PSAM4-GlyR in mouse sensory neurons produced behavioural hyposensitivity upon agonist administration, which was recovered upon agonist washout. Importantly, stable expression of the channel led to similar reversible behavioural effects even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM4-GlyR activation in acute and joint pain inflammation models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioural hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM4-GlyR activation decreased the excitability of human induced pluripotent stem-cell-derived sensory neurons and spontaneous activity due to a gain of function NaV1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable and reversible human-based chemogenetic system for the treatment of pain.

neuroscience↗