Importin α3 regulates chronic pain pathways in peripheral sensory neurons

Science ◽  
2020 ◽  
Vol 369 (6505) ◽  
pp. 842-846 ◽  
Author(s):  
Letizia Marvaldi ◽  
Nicolas Panayotis ◽  
Stefanie Alber ◽  
Shachar Y. Dagan ◽  
Nataliya Okladnikov ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sensory Neurons ◽  
Nuclear Import ◽  
Nucleocytoplasmic Transport ◽  
Dominant Negative ◽  
Peripheral Neurons ◽  
Pain Pathways ◽  
Peripheral Sensory Neurons ◽  
Control Pain ◽  
Peripheral Sensory

How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron–specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3–bound c-Fos and importin α3–deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.

scholarly journals Control of mechanical pain hypersensitivity through ligand-targeted photoablation of TrkB positive sensory neurons

2017 ◽  
Author(s):  
Rahul Dhandapani ◽  
Cynthia Mary Arokiaraj ◽  
Francisco J. Taberner ◽  
Paola Pacifico ◽  
Sruthi Raja ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Mechanical Allodynia ◽  
List Type ◽  
Light Touch ◽  
Peripheral Neurons ◽  
Necessary And Sufficient ◽  
Peripheral Sensory

SummaryMechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury. Mice in which TrkB-Cre expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.HighlightsTrkB+ neurons detect light touch under basal conditionsTrkB+ neurons convey mechanical allodynia in neuropathic pain statesA photosensitizing derivative of BDNF allows for photoablation of TrkB+ neuronsBDNF-guided photoablation reverses allodynia in multiple types of neuropathic pain

scholarly journals Loss of the liver X receptor LXRα/β in peripheral sensory neurons modifies energy expenditure

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Virginie Mansuy-Aubert ◽  
Laurent Gautron ◽  
Syann Lee ◽  
Angie L Bookout ◽  
Christine M Kusminski ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Sensory Neurons ◽  
Metabolic Regulation ◽  
Liver X Receptor ◽  
Peripheral Neurons ◽  
Nodose Ganglia ◽  
Physiological Adaptations ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory ◽  
Liver X Receptor Alpha

Peripheral neural sensory mechanisms play a crucial role in metabolic regulation but less is known about the mechanisms underlying vagal sensing itself. Recently, we identified an enrichment of liver X receptor alpha and beta (LXRα/β) in the nodose ganglia of the vagus nerve. In this study, we show mice lacking LXRα/β in peripheral sensory neurons have increased energy expenditure and weight loss when fed a Western diet (WD). Our findings suggest that the ability to metabolize and sense cholesterol and/or fatty acids in peripheral neurons is an important requirement for physiological adaptations to WDs.

scholarly journals AAV-PHP.S-mediated delivery of reporters to cranial ganglion sensory neurons

2021 ◽  
Author(s):  
Andoni I. Asencor ◽  
Gennady Dvoryanchikov ◽  
Pantelis Tsoulfas ◽  
Nirupa Chaudhari
Keyword(s):  
Sensory Neurons ◽  
Molecular Subtypes ◽  
Cranial Nerves ◽  
Receptive Fields ◽  
Dependent Manner ◽  
Cell Type ◽  
Peripheral Neurons ◽  
Light Sheet Microscopy ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

ABSTRACTBecause of their ease of use and low risk containment, Adeno-Associated Virus vectors are indispensable tools for much of neuroscience. Yet AAVs have been used relatively little to study the identities and connectivity of peripheral sensory neurons because methods to selectively target particular receptive fields or neuron types have been limited. The introduction of the AAV-PHP.S capsid with selective tropism for peripheral neurons (Chan et al., 2017) offered a solution, which we further elaborate here. We demonstrate using AAV-PHP.S with GFP or mScarlet reporters, that all cranial sensory ganglia, i.e. for cranial nerves V, VII, IX and X, are targeted. Pseudounipolar neurons of both somatic and visceral origin, but not satellite glia, are efficiently transduced rapidly and express the gene of interest within 1 week of injection. Fluorescent reporter proteins are transported into the central and peripheral axons of these sensory neurons, permitting visualization of terminals at high resolution, and/or in intact, cleared brain using light sheet microscopy. By combining a Cre-dependent reporter with the AAV-PHP.S capsid, we confirmed expression in a cell-type dependent manner for both anatomical and targeted functional analyses. The AAV-PHP.S capsid will be a powerful tool for mapping the receptive fields and circuits of molecular subtypes of many somatosensory, gustatory and visceral sensory neurons.SIGNIFICANCE STATEMENTAAV vectors have become an essential tool for visualizing, manipulating, and recoding from neurons of the central nervous system. However, the technology is not widely used for peripheral neurons because of several technical limitations. The AAV-PHP.S synthetic capsid, which targets peripheral neurons, was recently introduced (Chan et al., 2017). Here, we establish key parameters for using this virus, including which cells are transduced, the timing of expression in central and peripheral terminals, distant from neuronal somata, and the effectiveness of Cre-dependent constructs for cell type selective expression. This permits the use of AAV for constructing detailed anatomic and functional maps of the projections of molecular subtypes of peripheral sensory neurons.

scholarly journals Brain-derived neurotrophic factor derived from peripheral sensory neurons plays a critical role in pain chronification

2017 ◽  
Author(s):  
Shafaq Sikandar ◽  
Michael S. Minett ◽  
Joanne Lau ◽  
Queensta Millet ◽  
Sonia Santana-Varela ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Sensory Neurons ◽  
Knockout Mice ◽  
Normal Development ◽  
Critical Role ◽  
Primary Afferent ◽  
Mechanical Hypersensitivity ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

AbstractMultiple studies support the pro-nociceptive role of brain-derived neurotrophin factor (BDNF) in pain processes in the peripheral and central nervous system. We have previously shown that nociceptor-derived BDNF is implicated in inflammatory pain. Microglial-derived BDNF has also been shown to be involved in neuropathic pain. However, the distinct contribution of primary afferent-derived BNDF to chronic pain processing remains undetermined. In this study, we used Advillin-CreERT2 mice to delete Bdnf from all adult peripheral sensory neurons. Conditional BDNF knockouts were healthy with no sensory neuron loss. Behavioural assays and in vivo electrophysiology indicated that spinal excitability was normal. Following formalin inflammation or neuropathy with a modified Chung model, we observed normal development of acute pain behaviour, but a deficit in second phase formalin-induced nocifensive responses and a reversal of neuropathy-induced mechanical hypersensitivity during the later chronic pain phase in conditional BDNF knockout mice. In contrast, we observed normal development of acute and chronic neuropathic pain in the Seltzer model, indicating differences in the contribution of BDNF to distinct models of neuropathy. We further used a model of hyperalgesic priming to examine the contribution of primary afferent-derived BDNF in the transition from acute to chronic pain, and found that primed BDNF knockout mice do not develop prolonged mechanical hypersensitivity. Our data suggest that BDNF derived from sensory neurons plays a critical role in mediating the transition from acute to chronic pain.

Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

Neuroscience ◽  
2010 ◽  
Vol 169 (1) ◽  
pp. 449-454 ◽  
Author(s):  
C. König ◽  
O. Gavrilova-Ruch ◽  
G. Segond von Banchet ◽  
R. Bauer ◽  
M. Grün ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Sensory Neurons ◽  
Receptor Desensitization ◽  
Peripheral Sensory Neurons ◽  
Μ Opioid Receptor ◽  
Phosphoinositide 3 Kinase ◽  
Peripheral Sensory

scholarly journals A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons

Pain ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 2364-2372 ◽  
Author(s):  
Kalina Szteyn ◽  
Matthew P. Rowan ◽  
Ruben Gomez ◽  
Junhui Du ◽  
Susan M. Carlton ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Sensory Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Metabotropic Glutamate ◽  
Peripheral Sensory Neurons ◽  
Anchoring Protein ◽  
Peripheral Sensory

scholarly journals Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release

2021 ◽  
Vol 22 (16) ◽  
pp. 8826
Author(s):  
Wanzhi Wang ◽  
Miaomiao Kong ◽  
Yu Dou ◽  
Shanghai Xue ◽  
Yang Liu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Safety Concern ◽  
Unmet Need ◽  
Nociceptive Neurons ◽  
Neuropeptide Release ◽  
Selective Expression ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

scholarly journals Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

2020 ◽  
Vol 132 (4) ◽  
pp. 867-880 ◽  
Author(s):  
Doaa M. Mohamed ◽  
Mohammed Shaqura ◽  
Xiongjuan Li ◽  
Mehdi Shakibaei ◽  
Antje Beyer ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mineralocorticoid Receptor ◽  
Mineralocorticoid Receptors ◽  
Mineralocorticoid Receptor Antagonist ◽  
Aldosterone Synthase ◽  
Nociceptive Neurons ◽  
Processing Enzyme ◽  
Peripheral Sensory Neurons ◽  
Synthase Inhibitor ◽  
Peripheral Sensory

Abstract Background Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods In male Wistar rats (n = 5 to 8 per group) with Freund’s complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase–polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results In rats with Freund’s complete adjuvant–induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). Conclusions Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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