Biology subjects

Grabus, N. K.

Publications and source records attributed to Grabus, N. K..

3 recordsLinked to original sources

bioRxiv2026

Peripheral NaV1.7 modulation reveals divergent peripheral and central adaptations in persistent trigeminal pain

Trigeminal pain produces persistent facial hypersensitivity that is difficult to treat. Ion channels contribute to the pathology of trigeminal pain, but the consequences of their modulation remain poorly understood. We previously demonstrated that voltage-gated sodium channel Nav1.7 is a therapeutic target that can be indirectly modulated via interaction with collapsin mediated response protein 2 (CRMP2) to reduce membrane expression of Nav1.7 and trigeminal ganglion neuronal excitability. We used the Foramen Rotundum Inflammatory Constriction of the Trigeminal InfraOrbital Nerve (FRICT-ION) model of trigeminal neuropathic pain to characterize behavioral and supraspinal effects of indirectly modulating the peripheral CRMP2-Nav1.7 interaction via our novel Compound 194 (C194). FRICT-ION produced mechanical and cold allodynia, which were reduced by C194, but had no effect on non-evoked affective behaviors. Despite behavioral improvement, C194 did not normalize heightened glutamatergic activity in the parabrachial nucleus (PBN), revealing a dissociation between behavioral analgesia and activity of a central pain circuit. These findings extend mechanistic studies of C194 in the trigeminal system and demonstrate efficacy of CRMP2-Nav1.7 disruption in modulating facial pain-like behavior. These results support the CRMP2-Nav1.7 axis as a promising therapeutic target while highlighting the need to define how peripheral and central adaptations interact to shape persistent facial pain.

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↗

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↗