Biology subjects

Stratton, H. J.

Publications and source records attributed to Stratton, H. J..

6 recordsLinked to original sources

bioRxiv2026

Multimodal transcriptomics and calcium imaging reveal a novel subset of polymodal nociceptors expressing the interleukin 1 receptor in mice

We previously established that sensory neurons in the mouse dorsal root ganglia (DRG) express a functional receptor for the proinflammatory cytokine interleukin (IL)-1. We also demonstrated that deletion of the IL-1 receptor type 1 gene, Il1r1, in TRPV1-expressing (+) neurons prevented pain in models of chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis and osteoarthritis. Here, we found a marked sex difference in the abundance of IL-1R1+ neurons, which represented approximately 10% of all DRG neurons in females but only 5% in males. However, male mice exhibited stronger, longer-lasting mechanical hypersensitivity than females after IL-1{beta} injection into the cerebrospinal fluid. In vivo calcium imaging revealed that IL-1{beta}- responsive DRG neurons responded to cutaneous mechanical and capsaicin stimulation. By integrating spatial transcriptomics with single-cell RNA sequencing (scRNA-Seq), we identified a gene signature uniquely marking IL-1R1+ neurons, including genes such as Ada, Cysltr2, Gpr139, Htr1a, Htr1f, Il31ra, Nppb, Npy2r, Nts, P2rx2, Pde4c, and Sst, with Ada and Sst validated at the protein level. Omics analysis revealed that IL-1R1+ DRG neurons form a subset of non-peptidergic type 3 (NP3) sensory neurons, which are linked to inflammatory pain and itch. However, Il1r1 deletion did not affect itch responses to serotonin, histamine, or chloroquine, and these mediators failed to induce calcium activity in IL-1{beta}-responsive DRG neurons. Finally, scRNA-seq identified several genes upregulated in NP3 neurons after IL-1{beta} injection, including Alkal2, Bdnf, and Lcn2, associated with chronic inflammatory pain. Thus, our study unveils novel markers for IL-1R1+ nociceptors and reaffirms their selective role in inflammatory pain.

neuroscience↗

bioRxiv2024

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

neuroscience↗

bioRxiv2023

Functional Sexual Dimorphism in Human Nociceptors

The recent demonstration of differences in transcript expression in human post-mortem sensory neurons suggests the possibility of sexually dimorphic pain mechanisms. To date, however, the concept of "male" and "female" nociceptors has not been demonstrated at a functional level. We now report sensitization of female, but not male, human nociceptors by prolactin revealing a female-selective mechanism that can be exploited to improve the treatment of pain in women.

neuroscience↗

bioRxiv2022

Identification and targeting of a unique NaV1.7 domain driving chronic pain

Despite identification of several small molecules directly targeting the voltage-gated sodium channel NaV1.7, none has been clinically successful. We reported that preventing addition of a small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and was antinociceptive in rodents. Here, we discovered a 15 amino acid CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight voltage-gated sodium channel isoforms decreased tetrodotoxin-sensitive NaV1.7 currents in rodent sensory neurons. A cell-penetrant version of NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 localization, reduced spinal neurotransmitter release, and reversed mechanical allodynia in a rat spared nerve injury model of neuropathic pain. Interfering with NaV1.7-CRMP2 coupling did not produce motor impairment and spared thermal, inflammatory, and post-surgical nociception. As proof-of-concept for NaV1.7-targeted gene therapy, we found that NaV1.7-CRS packaged into an adeno-associated virus recapitulated the effects on NaV1.7 function in both rodent and rhesus macaque sensory neurons and both reversed and prevented the development of mechanical allodynia in a neuropathic pain model in male and female rodents. One Sentence SummaryA novel regulatory domain on the voltage gated sodium channel NaV1.7 that can be targeted to produce analgesia.

neuroscience↗

bioRxiv2020

SARS-CoV-2 Spike protein hijacks VEGF-A/Neuropilin-1 receptor signaling to induce analgesia

Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2s Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) - a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A silencing of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.

neuroscience↗

bioRxiv2020

Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific NaV1.7 regulation in the pathogenesis of chronic neuropathic pain

The sodium channel NaV1.7 is a master regulator of nociceptive neuronal firing. Mutations in this channel can result in painful conditions as well as produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting NaV1.7 has not yet produced a clinical drug. Recent work has illuminated the NaV1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Amongst the regulators of NaV1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at Lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound NaV1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2K374A/K374A) mice in which Lys374 was replaced with Ala. CRMP2K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral NaV1.7 is a hallmark of chronic, but not physiological, neuropathic pain.

neuroscience↗