Biology subjects

Calderon-Rivera, A.

Publications and source records attributed to Calderon-Rivera, A..

4 recordsLinked to original sources

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↗

bioRxiv2023

Neuropilin-1 is a co-receptor for NGF and TrkA-evoked pain

Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain yet, failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a co-receptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 is coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppress NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibits NGF/TrkA signaling, whereas NRP1 overexpression enhances signaling. NGF binds NRP1 with high affinity and interacts with and chaperones TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggests that C-terminal R/KXXR/K NGF motif interacts with extracellular "b" NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G Alpha Interacting Protein C-terminus 1 (GIPC1) scaffolds NRP1 and TrkA to myosin VI and colocalizes in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogates NGF-evoked excitation of nociceptors and pain-like behavior. NRP1 is a nociceptor-enriched co-receptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via the GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited non-opioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain. SummaryNeuropilin-1 and G Alpha Interacting Protein C-terminus 1 are necessary for nerve growth factor-evoked pain and are non-opioid therapeutic targets for chronic pain.

neuroscience↗

bioRxiv2023

Intranasal CRMP2-Ubc9 Inhibitor Regulates NaV1.7 to Alleviate Trigeminal Neuropathic Pain

Dysregulation of voltage-gated sodium NaV1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/NaV1.7 interaction and increased functional activity of NaV1.7. Targeting this feed-forward regulation, we developed compound 194, which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of NaV1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we employed a comprehensive array of investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of NaV1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a, Dpysl2, and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and NaV1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/NaV1.7 interaction, impeded NaV1.7 diffusion on the plasma membrane, and subsequently diminished NaV1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve (CCI-ION), 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating NaV1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.

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↗