Biology subjects

Nelson, T. S.

Publications and source records attributed to Nelson, T. S..

11 recordsLinked to original sources

bioRxiv2026

A mouse model of myotonic dystrophy type 1 exhibits pain-like behavior and peripheral nociceptor hyperexcitability

Pain is a prevalent and disabling symptom of myotonic dystrophy type 1 (DM1), yet its underlying mechanisms remain poorly understood. Using HSA LR20b transgenic mice, we found multimodal mechanical and thermal hypersensitivity. Whole-cell electrophysiological recordings demonstrated depolarized resting membrane potentials and increased action potential firing selectively in small- and medium-diameter dorsal root ganglion neurons. These findings identify peripheral nociceptor sensitization as a potential mechanism contributing to pain in DM1.

neuroscience↗

bioRxiv2026

NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease

Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson's disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited. Safinamide is one of the few drugs reported to improve pain in PD, but the mechanism underlying this effect is unknown. Here, we show that nigrostriatal neurodegeneration produces persistent hyperexcitability of primary sensory neurons associated with dysregulation of the voltage-gated sodium channel NaV1.7. In a brain-restricted 6-hydroxydopamine (6-OHDA) model, small-diameter dorsal root ganglion (DRG) neurons exhibited increased sodium current density and altered voltage-dependent inactivation, with the excess current eliminated by selective NaV1.7 blockade. Safinamide directly inhibited a NaV1.7-dependent component of sensory neuron sodium current and reversed established pain-like behaviors. Pharmacological disruption of NaV1.7 regulation by collapsin response mediator protein 2 (CRMP2) normalized DRG hyperexcitability and reversed mechanical and thermal hypersensitivity, whereas genetic disruption of the NaV1.7 CRMP2 regulatory sequence prevented the development of 6-OHDA-induced pain-like behaviors for up to 30 weeks despite preservation of the Parkinsonian motor phenotype. Transcriptomic profiling of human PD DRGs revealed limited global transcriptional remodeling with selective alterations in genes associated with sensory neuron excitability. Together, these findings demonstrate that dopaminergic neurodegeneration initiated within the brain is sufficient to drive persistent peripheral sensory neuron dysfunction and identify CRMP2-dependent regulation of NaV1.7 as a therapeutic target for Parkinsonian pain.

neuroscience↗

bioRxiv2026

NRP1 regulates basal nociception: characterization of a peptidergic-specific NRP1 knockout mouse

Neuropilin-1 (NRP1) is a single pass transmembrane glycoprotein that can form a receptor complex with several tyrosine kinase receptors, including the vascular endothelial growth factor (VEGF) receptor. Previous studies have reported that binding of VEGFA to this receptor complex elicits mechanical allodynia and thermal hyperalgesia through potentiation of voltage-gated sodium and calcium channel activity. We find that Nrp1 mRNA and protein is widely distributed in naive mouse and rat DRG neurons, including peptidergic afferents. A CGRPcreER: NRP1fl/fl transgenic mice was generated to investigate the role of peptidergic NRP1 in basal nociception. Following in vivo loss of NRP1, while mice are hyposensitive to both noxious heat and mechanical stimuli. Under normal conditions, VEGFA elicits mechanical hypersensitivity, an effect that was absent in our NRP1 knockout mouse. Furthermore, VEGFA induced neuronal hyperexcitability was lost in CGRP expressing neurons isolated from this NRP1 knockout mouse. This study validates the NRP1 knockout mouse and confirms previous findings that VEGFA, often released during pathological pain conditions, requires peptidergic NRP1. Interestingly, we find that in the absence of ongoing injury or inflammation, peptidergic NRP1 regulates basal nociception and pain-like behaviors.

neuroscience↗

bioRxiv2025

Amygdalar Calcitonin Gene-Related Peptide Driven Effects of Cold Sensitivity Induced by Peripheral Neuropathy in Mice

The central nucleus of the amygdala (CeA) is a critical regulator of nociception, and its role in pain modulation depends on factors such as hemispheric location, neuropeptide release, and experimental model. Calcitonin gene-related peptide (CGRP) is a potent neuropeptide modulator within the CeA. Previous research has demonstrated its CeA nociceptive role in migraine, visceral, arthritic, and inflammatory pain murine models. The contribution of CeA CGRP to neuropathic pain is unclear. This study examined the effects of CGRP and its receptor antagonist, CGRP 8-37, in the CeA on mechanical and cold sensitivity in two mouse models of neuropathic pain: chemotherapy-induced peripheral neuropathy (CIPN) mediated by paclitaxel (PTX) and injury-induced neuropathy through the spared nerve injury (SNI) model. Mechanical and cold sensitivity were measured using the hindpaw von Frey and topical acetone drop assays, respectively. Neither CGRP nor CGRP 8-37 in the CeA had any significant effect on mechanical sensitivity in either neuropathic pain model. In the SNI-treated mice, CGRP infusion into either the left or right CeA reduced cold sensitivity in the left and right SNI-treated hindpaw, while CGRP 8-37 infusion into the left or right CeA increased cold sensitivity in the right SNI-treated hindpaw only. In PTX-treated mice, CGRP infusion into the left or right CeA decreased cold sensitivity of the contralateral paw only. These results suggest that CGRP in the CeA influences pain modulation in a complex manner that depends not only on the hemisphere and injury site, but also on the underlying cause of the neuropathic condition. PERSPECTIVEThis article presents the anti-nociceptive properties of calcitonin gene-related peptide (CGRP) signaling within the central nucleus of the amygdala during neuropathic pain-like conditions in mice. This dataset can serve to guide novel drug development for treating chronic neuropathic pain conditions. HIGHLIGHTSO_LILateralization of the central nucleus of the amygdala (CeA) is pain-model dependent C_LIO_LICGRP signaling within the CeA is correlated with decreased cold sensitivity C_LIO_LIDifferent neuropathic etiologies yield differences in CGRP responsiveness C_LI

neuroscience↗

bioRxiv2025

Parabrachial bombesin receptor subtype 3 neurons facilitate heat pain in persistent inflammation

The parabrachial nucleus (PBN) is a critical hub for pain processing that acts as a switchboard for nociceptive signals, relaying sensory information to forebrain regions that integrate the sensory and affective dimensions of pain. Although the PBN is well established as a key regulator of pain, the remarkable heterogeneity of its neuronal populations has hindered efforts to identify specific cell types responsible for distinct aspects of pain processing. Here, we identify bombesin receptor subtype 3 (Brs3)-expressing neurons as a distinct glutamatergic PBN subpopulation involved in heat hypersensitivity associated with persistent pain. Using Fos expression analysis and in vivo calcium imaging, we demonstrate that Brs3 neurons exhibit heightened activity in response to heat stimulation following an inflammatory insult or neuropathic injury. Inhibition of Brs3 neurons effectively reduces heat, but not mechanical, hypersensitivity induced by both inflammatory and neuropathic pain, suggesting a specific role in processing heat hypersensitivity. Ablation of parabrachial Brs3 neurons prior to induction of pain also selectively prevents the development of heat hypersensitivity induced by persistent inflammation in mice. Brs3-expressing neurons encompass multiple previously identified pain-related PBN subpopulations, including those expressing the mu opioid receptor (Oprm1), tachykinin 1 receptor (Tacr1), and neuropeptide Y Y1 receptor (Npy1r), positioning Brs3 as a potential unifying marker of heat hypersensitivity circuits. These findings provide new insight into the organization of pain-processing networks in the PBN and highlight Brs3 neurons as a crucial population for heat pain.

neuroscience↗

bioRxiv2024

A synthetic potassium channel reduces oxidative stress 1 via cellular adaptronics

Aerobic metabolism is crucial for human life but reactive oxygen species (ROS) byproducts cause cellular toxicity. Although antioxidant defenses usually maintain ROS levels within a safe range, ROS production can exceed the buffering capacity of cells, causing oxidative stress and disease. Inspired by the principle of adaptronics, we created a synthetic potassium channel that senses cellular ROS levels and mitigates oxidative stress by modulating membrane potential. Engineered from TASK1 channel, ROSTASK1 is sensitive to supraphysiological ROS levels, imposing restorative membrane potential changes on cells or organelles under oxidative stress. We also engineered a blue-light sensitive ROSTASK1 to achieve optogenetic control. In proof-of-concept experiments, mitochondrially-delivered ROSTASK1 rescued ROS overproduction in myoblasts from a Leigh syndrome patient and ROSTASK1 abolished chronic pain-like behavior in mouse models of inflammation and nerve injury. Thus, by functioning as both a sensor and modulator of ROS levels, ROSTASK1 provides a self-healing system during oxidative stress.

biophysics↗

bioRxiv2024

Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors

Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the NaV1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.

neuroscience↗

bioRxiv2024

Uncoupling the CRMP2-CaV2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis model

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate CaV2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.

neuroscience↗

bioRxiv2024

A parabrachial hub for the prioritization of survival behavior

Long-term sustained pain in the absence of acute physical injury is a prominent feature of chronic pain conditions. While neurons responding to noxious stimuli have been identified, understanding the signals that persist without ongoing painful stimuli remains a challenge. Using an ethological approach based on the prioritization of adaptive survival behaviors, we determined that neuropeptide Y (NPY) signaling from multiple sources converges on parabrachial neurons expressing the NPY Y1 receptor to reduce sustained pain responses. Neural activity recordings and computational modeling demonstrate that activity in Y1R parabrachial neurons is elevated following injury, predicts functional coping behavior, and is inhibited by competing survival needs. Taken together, our findings suggest that parabrachial Y1 receptor-expressing neurons are a critical hub for endogenous analgesic pathways that suppress sustained pain states.

neuroscience↗

bioRxiv2023

Parabrachial Calca neurons drive nociplasticity

Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBN Calca neurons from releasing neurotransmitter or directly stimulating them we demonstrate that activation of Calca neurons is both necessary for the manifestation of chronic pain after nerve ligation and is sufficient to drive nociplasticity in wild-type mice. Aversive stimuli such as exposure to nitroglycerin, cisplatin, or LiCl can drive nociplasticity in a Calca-neuron-dependent manner. Calcium fluorescence imaging reveals that nitroglycerin activates PBN Calca neurons and potentiates their responses to mechanical stimulation. The activity and excitability of Calca neurons increased for several days after aversive events, but prolonged nociplasticity likely occurs in downstream circuitry.

neuroscience↗

bioRxiv2022

Endogenous μ-opioid - neuropeptide Y Y1 receptor synergy silences chronic postoperative pain

Tissue injury creates a delicate balance between latent pain sensitization (LS) and compensatory endogenous analgesia. Inhibitory G protein-coupled receptor (GPCR) interactions that oppose LS, including -opioid receptor (MOR) and neuropeptide Y Y1 receptor (Y1R) activity, persist in the spinal cord dorsal horn (DH) for months, even after the resolution of normal pain thresholds. Here, we demonstrate that following recovery from surgical incision, a potent endogenous analgesic synergy between MOR and Y1R activity persists within DH interneurons to reduce the intensity and duration of latent postoperative hyperalgesia and ongoing pain. Failure of such endogenous GPCR signaling to maintain LS in remission may underlie the transition from acute to chronic pain states.

neuroscience↗