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Central sensitization caused by disinhibition of spinal cord circuits is a key mechanism of mechanical allodynia in neuropathic pain. Despite intense efforts, the molecular mechanisms that drive disinhibition and induce allodynia after peripheral nerve injury remain unclear. Using the spared-nerve injury (SNI) model of allodynia, we here demonstrate that SNI induces disinhibition of spinal nociceptive circuits by triggering homeostatic synaptic plasticity. Specifically, SNI-triggereddoi:10.1101/2022.01.10.475704 fatcat:x2cljjbeojfgnozrlmr2pnzj7u
more »... plasticity suppresses the inhibitory outputs of parvalbumin-positive (PV+) interneurons that form synapses on both primary afferent terminals and excitatory interneurons, causing hyperactivation of the nociceptive pathway. Using genetic manipulations, we identified the retinoic acid receptor RARα as the key mediator of the homeostatic synaptic plasticity underlying this synaptic disinhibition. Deletion of RARα in PV+ neurons blocked SNI-induced spinal disinhibition, central sensitization, and allodynia. Moreover, deletion of RARα in spinal PV+ neurons or application of an RARα antagonist in the spinal cord prevented the development of SNI-induced mechanical allodynia. Together, our results reveal a molecular mechanism of neuropathic pain whereby homeostatic plasticity causes the mis-direction of tactile information flow to ascending nociceptive pathways following peripheral nerve injury.
An amygdalar neural ensemble that encodes the unpleasantness of pain Gregory ...doi:10.1126/science.aap8586 pmid:30655440 pmcid:PMC6450685 fatcat:np55pvfs7vew5dmn4l3d3yfb4q
Nerve growth factor/tropomyosin receptor kinase A (NGF/TrkA) signaling plays a key role in neuronal development, function, survival, and growth. The pathway is implicated in neurodegenerative disorders including Alzheimer's disease, chronic pain, inflammation, and cancer. NGF binds the extracellular domain of TrkA, leading to the activation of the receptor's intracellular kinase domain. TrkA signaling is highly dynamic, thus mechanistic studies would benefit from a tool with high spatial anddoi:10.1101/287409 fatcat:y5lbchaje5earpw2ops7k4qlaa
more »... poral resolution. Here we present the design and evaluation of four strategies for light-inducible activation of TrkA in the absence of NGF. Our strategies involve the light-sensitive protein Arabidopsis cryptochrome 2 (CRY2) and its binding partner CIB1. We demonstrate successful recapitulation of native NGF/TrkA functions by optical induction of plasma membrane recruitment and homo-interaction of the intracellular domain of TrkA. This approach activates PI3K/AKT and Raf/ERK signaling pathways, promotes neurite growth in PC12 cells, and supports the survival of dorsal root ganglion neurons in the absence of NGF. This ability to activate TrkA using light bestows high spatial and temporal resolution for investigating NGF/TrkA signaling.
., Scherrer, G., & Julius, D. (2009). Cellular and Molecular Mechanisms of Pain. Cell. Fillingim, R. B. (2010). Sex, Gender, and Pain. In The Senses: A Comprehensive Reference (Vol. 5, pp. 253-257). ...doi:10.1016/j.cell.2009.09.028 pmid:19837031 pmcid:PMC2852643 fatcat:nii7r6nw7fgfbjgs76ol4b7t4u
Valeria Vá squez 1 , Gregory Scherrer 2 , and Miriam B. ...doi:10.1016/j.cub.2014.05.011 pmid:24937283 pmcid:PMC7341064 fatcat:pdv6qqherzaphjyw5y6ljfrrf4
Journal of Neurophysiology, 71(2), pp.802-807. 812 813 Corder, G., Castro, D.C., Bruchas, M.R. and Scherrer, G., 2018. Endogenous and exogenous 814 opioids in pain. ... (Wang et al., 2018) 702 703 PV/ DOR Immunohistochemistry 704 A previously described immunostaining protocol was employed (Bardoni et al., 2014; Scherrer et 705 al., 2009). ...doi:10.1101/525782 fatcat:e6immffqefgorm4egtmo6qfz5i
, 2017; Scherrer et al., 2009) . ... Gré gory Scherrer (firstname.lastname@example.org) . ...doi:10.1016/j.neuron.2018.03.002 pmid:29576387 pmcid:PMC5896237 fatcat:t3hefs666nco5ftvvwdybsjyt4
G-protein-coupled receptors (GPCRs) regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Receptor internalization is commonly observed following agonist binding and activation. Receptor trafficking events have been well characterized in cell systems, but the in vivo significance of GPCR internalization is still poorly understood. To address this issue, we have developed an innovative knock-in mouse model, where an opioid receptor is directlydoi:10.1007/978-1-4939-1708-2_7 pmid:25293318 pmcid:PMC4372127 fatcat:5fknhhz2rvdinex3vzaeqfbqtu
more »... sible in vivo. These knockin mice express functional fluorescent delta opioid receptors (DOR-eGFP) in place of the endogenous receptor, and these receptors are expressed at physiological levels within their native environment. DOR-eGFP mice have proven to be an extraordinary tool in studying receptor neuroanatomy, real-time receptor trafficking in live neurons, and in vivo receptor internalization. We have used this animal model to determine the relationship between receptor trafficking in neurons and receptor function at a behavioral level. Here, we describe in detail the construction and characterization of this knockin mouse. We also outline how to use these mice to examine the behavioral consequences of agonist-specific trafficking at the delta opioid receptor. These techniques are potentially applicable to any GPCR, and highlight the powerful nature of this imaging tool.
In this issue of Neuron, Stoeber et al. (2018) report a biosensor resolving the spatiotemporal organization of opioid receptor activation in living neurons. They delineate novel signaling mechanisms in endosomes and Golgi differentially engaged by opioid peptides and drugs.doi:10.1016/j.neuron.2018.05.035 pmid:29879387 pmcid:PMC6492023 fatcat:6m67y2o6ubayxh7apaa4baunqi
., 2014; Scherrer et al., 2009) . ... A knockin mouse line expressing GFP-fused DORs (Scherrer et al., 2006) was used to probe for the presence of DOR proteins in sections stained for parvalbumin proteins. ...doi:10.7554/elife.45146 pmid:31099753 pmcid:PMC6541437 fatcat:zwnxvnalbrdovjsb3zktmj4qhe
In this issue of Neuron, Santello and Nevian (2015) report HCN channel plasticity and increased temporal summation in layer 5 ACC neurons following nerve injury. They are able to restore HCN channel function and reduce behavioral hypersensitivity with selective serotonin receptor targeting.doi:10.1016/j.neuron.2015.03.045 pmid:25856476 pmcid:PMC7341066 fatcat:lcgo7345dnbehohi73bjcrtgra
Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Following chronic opioid treatment and peripheral nerve injury (PNI) microglia in the spinal cord display similar morphological responses. Consistent with this observation, functional studies have suggested that microglia activated by PNI ordoi:10.1101/2021.12.29.473853 fatcat:evrpfmq2bzdbfa6fa6b52nccda
more »... ids engage common molecular mechanisms to induce hypersensitivity. Here we conducted deep RNA sequencing of acutely isolated spinal cord microglia from male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple OIH and PNI models. Following PNI, we identify a common early proliferative transcriptional event across models that precedes the upregulation of histological markers of activation, followed by a delayed and injury-specific transcriptional response. Strikingly, we found no such transcriptional responses associated with opioid-induced microglial activation, consistent with histological data indicating that microglia number remain stable during morphine treatment. Collectively, these results reveal the diversity of pain-associated microglial transcriptomes and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other CNS pathologies.
Graphical Abstract Highlights d A system for optogenetic control of spinal circuits using offthe-shelf components d Bidirectional control of SOM+ neurons indicates primary role in mechanosensation d Temporally sparse SOM+ neuron stimulation reveals role in itch sensationdoi:10.1016/j.celrep.2016.10.010 pmid:27806306 pmcid:PMC5507199 fatcat:k4s2sxiamjb55oyntksshcohyq
Leukotriene B 4 (LTB 4 ) is a pro-inflammatory lipid mediator generated by the enzymes 5lipoxygenase (5-LO) and LTA 4 -hydrolase. LTB 4 signals primarily through its G protein-coupled receptor BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. Here we tested the hypothesis that pharmacological inhibition of BLT1 diminishes abdominaldoi:10.1016/j.atherosclerosis.2009.11.031 pmid:20035940 pmcid:PMC2862127 fatcat:eyectpf4pbgnzhjgwkoxxq6cai
more »... ortic aneurysm (AAA) formation, a major complication associated with atherosclerotic vascular disease. Chow-fed Apoe -/mice were treated with a 4 week infusion of Angiotensin II (AngII, 1000 ng/kg/min) beginning at 10 weeks of age, in a well-established murine AAA model. Administration of the selective BLT1 antagonist CP-105,696 beginning simultaneously with AngII infusion reduced the incidence of AAA formation from 82% to 40% (p<0.05). There was a concordant reduction in maximal aortic diameter from 2.35 mm to 1.56 mm (p<0.05). While administration of the antagonist on day 14 after the onset of AngII infusion diminished lesional macrophage accumulation, it did not significantly alter the size of AAA by day 42. Thus, pharmacological inhibition of BLT1 may ultimately hold clinical promise, but early intervention may be critical.
Graphical Abstract Highlights d eCB-LTD is induced specifically at corticostriatal, but not thalamostriatal, synapses d CB1 receptor expression levels are responsible for input specificity d eCB-LTD in the striatum is present independent of postsynaptic SPN subtype d Coactivation of dopamine receptors modulates eCB-LTD expression in the striatum SUMMARY Changes in basal ganglia plasticity at the corticostriatal and thalamostriatal levels are required for motor learning.doi:10.1016/j.celrep.2014.12.005 pmid:25543142 pmcid:PMC4286501 fatcat:5xsyiymo5vf45g6k4irk3vshei
more »... longterm depression (eCB-LTD) is known to be a dominant form of synaptic plasticity expressed at these glutamatergic inputs; however, whether eCB-LTD can be induced at all inputs on all striatal neurons is still debatable. Using region-specific Cre mouse lines combined with optogenetic techniques, we directly investigated and distinguished between corticostriatal and thalamostriatal projections. We found that eCB-LTD was successfully induced at corticostriatal synapses, independent of postsynaptic striatal spiny projection neuron (SPN) subtype. Conversely, eCB-LTD was only nominally present at thalamostriatal synapses. This dichotomy was attributable to the minimal expression of cannabinoid type 1 (CB1) receptors on thalamostriatal terminals. Furthermore, coactivation of dopamine receptors on SPNs during LTD induction re-established SPN-subtype-dependent eCB-LTD. Altogether, our findings lay the groundwork for understanding corticostriatal and thalamostriatal synaptic plasticity and for striatal eCB-LTD in motor learning.
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