Biology subjects

Shiers, S. I.

Publications and source records attributed to Shiers, S. I..

5 recordsLinked to original sources

bioRxiv2026

Prolactin Receptor Long Isoform ΔS1 Expression is Reduced in the Dorsal Root Ganglia of Humans with Chronic Pain

Prolactin receptor (PRLR) isoforms, specifically the short (PRLR-S) and long (PRLR-L), are differentially expressed in pathological conditions and may be involved in the induction and maintenance of pain in females. PRLR sex-dependent actions are well studied in rodent models of chronic pain, but the translatability of these findings have only been assessed in electrophysiology studies that found consistent results with previous sex differences described in mice. To increase our understanding of the sexual dimorphic nature of prolactin actions on sensory neurons and our knowledge of how this body of work applies to the human nervous system, we characterized the expression of the short and long isoforms of PRLR with RNAscope in situ hybridization in human dorsal root ganglion (DRG) neurons. Based on data in mice, we hypothesized PRLR-S and PRLR-L would be equally expressed in human DRG neurons, with higher expression in females. To test this, we used DRG tissues recovered from male and female organ donors and cervix as a positive control. Our results demonstrated human DRG neurons express more PRLR-L, specifically transcript variant 6 ({Delta}S1), than PRLR-S in both sexes and that female donors had a higher expression of PRLR overall. In DRGs from female organ donors with a history of chronic pain we observed less PRLR-L expression, a finding consistent with previous studies in pain models in female mice. Expression for both PRLR isoforms in cervix was consistent with previous reports. An analysis of previously published RNA sequencing studies on human DRGs revealed that PRLR expression is confined mostly to TRPV1-positive nociceptors in humans, consistent with our RNAscope-based findings. We conclude that the PRLR-L ({Delta}S1) form is the major isoform expressed in human DRG neurons, that this expression is higher in females than in males, and that PRLR-L ({Delta}S1) expression is suppressed in chronic pain conditions in females.

neuroscience↗

bioRxiv2026

History of opioid use disorder correlates with altered neuroimmune signatures in the human dorsal root ganglia

Understanding mechanisms for the negative reinforcing effects of opioids are fundamental to improving patient care. Using human dorsal root ganglia (DRG) from donors with and without opioid use disorder (OUD), we set out to examine functional and molecular correlates of chronic opioid use. At a molecular level, we detected disrupted immune signatures throughout cells in the peripheral nervous system (PNS), spanning glial-neuroimmune interactions to changes in non-neuronal senescence. At the physiological level these changes are paired with sensitization of DRG sensory neurons. Our findings reveal a neuro-inflammatory state in the PNS of individuals with OUD. Targeting therapeutics towards these PNS-based mechanisms could be an approach to alleviating the negative reinforcing effects of opioids.

neuroscience↗

bioRxiv2026

Chronic lower limb pain is not associated with a loss of inhibitory neurons in the human lumbar spinal dorsal horn

The spinal dorsal horn is the primary processing site of nociceptive sensory input from the periphery. Excitatory spinal interneurons releasing glutamate can amplify this information before it is sent to the brain, whereas inhibitory neurons releasing GABA and/or glycine can suppress the outflow of nociceptive signals. An imbalance favoring excitation is thought to underlie certain aspects of chronic pain. Although rodent studies have identified spinal mechanisms underlying hyperalgesia and allodynia, little is known about the anatomical changes associated with chronic pain in the human spinal cord, a gap in knowledge we sought to address in this study. Using immunohistochemistry and in situ hybridization on lumbar spinal cord tissue recovered from organ donors, we characterized neuronal size and density across the human dorsal horn and confirmed the presence of the human equivalent of the lateral spinal nucleus in many individuals. Chronic lower limb pain was not associated with changes in neuronal density in the dorsal horn. Likewise, the ratio of excitatory (SLC17A6+) to inhibitory (PAX2+) neurons remained consistent across laminae for age, sex and chronic pain state, providing no evidence for selective loss of inhibitory neurons with chronic pain in humans. We found no differences in the size or density of the postsynaptic markers Homer1 and gephyrin between groups, suggesting glutamatergic and GABAergic postsynaptic sites remain structurally stable. These findings provide a thorough evaluation of cellular anatomy of the human dorsal horn and form a foundation for future studies investigating neuronal changes that may contribute to chronic pain in humans.

neuroscience↗

bioRxiv2024

VLK drives extracellular phosphorylation of EphB2 to govern the EphB2-NMDAR interaction and injury-induced pain

Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families, yet the significance of these kinases is underexplored. Here, we find that the presynaptic release of the tyrosine directed-ectokinase, Vertebrate Lonesome Kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses, for phosphorylation of the ectodomain of EphB2, and for injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is found in synaptic vesicles, and is released from neurons in a SNARE-dependent fashion. VLK is expressed by nociceptive sensory neurons where presynaptic sensory neuron-specific knockout renders mice impervious to post-surgical pain, without changing proprioception. VLK defines an extracellular mechanism that regulates protein-protein interaction and non-opioid-dependent pain in response to injury. One-Sentence SummarySynaptic protein-protein interactions and pain are regulated by the presynaptic release of the extracellular kinase VLK in the spinal cord.

neuroscience↗

bioRxiv2020

Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain

Persistent tactile pain is a poorly managed symptom of inflammatory and neuropathic injury. To develop therapies for this maladaptive sensation, the underlying molecular mediators must be identified. Using knockout mice and pharmacological inhibitors, we identified transient receptor canonical 5 (TRPC5) as a key contributor to the persistent tactile pain that occurs in many inflammatory and neuropathic preclinical rodent models. TRPC5 inhibition was effective in injuries associated with elevated levels of the bioactive phospholipid lysophosphatidylcholine (LPC). Exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain. In vitro, LPC activated both homomeric mouse and human TRPC5 channels, which upon examination of human dorsal root ganglia tissue, were expressed in 75% of human sensory neurons. Based on these results, TRPC5 inhibitors should be pursued as personalized therapy for spontaneous and tactile pain in conditions where elevated LPC is a biomarker.

neuroscience↗