Neonatal Injury Evokes Persistent Deficits in Dynorphin Inhibitory Circuits within the Adult Mouse Superficial Dorsal Horn

Brewer, Chelsie L; Li, Jie; O’Conor, Keith T; Serafin, Elizabeth K; Baccei, Mark L.

doi:10.1523/jneurosci.0029-20.2020

Cited by 19 publications

(11 citation statements)

References 66 publications

(103 reference statements)

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“…The Pdyn dorsal, inhibitory family was comprised of Inhib-9, Inhib-10, and Inhib-11 and expressed markers suggestive of a role in chemical itch 52,61,[73][74][75][76][77] . Each of these clusters expressed Pdyn, while Inhib-10 also expressed Gal and Mlxipl and Inhib-11 also expressed Gal only.…”

Section: Merged and Integrated Multi-study Analysismentioning

confidence: 99%

A harmonized atlas of mouse spinal cord cell types and their spatial organization

et al. 2021

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Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases of the mouse spinal cord have been published in recent years but have not been integrated together. Here, we generate an atlas of spinal cell types based on single-cell transcriptomic data, unifying the available datasets into a common reference framework. We report a hierarchical structure of postnatal cell type relationships, with location providing the highest level of organization, then neurotransmitter status, family, and finally, dozens of refined populations. We validate a combinatorial marker code for each neuronal cell type and map their spatial distributions in the adult spinal cord. We also show complex lineage relationships among postnatal cell types. Additionally, we develop an open-source cell type classifier, SeqSeek, to facilitate the standardization of cell type identification. This work provides an integrated view of spinal cell types, their gene expression signatures, and their molecular organization.

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Section: Merged and Integrated Multi-study Analysismentioning

confidence: 99%

A harmonized atlas of mouse spinal cord cell types and their spatial organization

et al. 2021

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“…We used the lipophilic dye Fast-DiI as a “universal” retrograde tracer of spinal projection neurons. Although Fast-DiI has been employed for the identification of spinoparabrachial neurons in functional studies [ 34 – 36 ], to our knowledge, the spinal distribution of labeled neurons has not been evaluated histologically in the mouse. Previous neuroanatomical analysis of spinopara-brachial neurons in the mouse was conducted using the retrograde tracer cholera toxin B (CTB) [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting the somatosensory system with AAV9 and AAV2retro viral vectors

et al. 2022

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Adeno-associated viral (AAV) vectors allow for site-specific and time-dependent genetic manipulation of neurons. However, for successful implementation of AAV vectors, major consideration must be given to the selection of viral serotype and route of delivery for efficient gene transfer into the cell type being investigated. Here we compare the transduction pattern of neurons in the somatosensory system following injection of AAV9 or AAV2retro in the parabrachial complex of the midbrain, the spinal cord dorsal horn, the intrathecal space, and the colon. Transduction was evaluated based on Cre-dependent expression of tdTomato in transgenic reporter mice, following delivery of AAV9 or AAV2retro carrying identical constructs that drive the expression of Cre/GFP. The pattern of distribution of tdTomato expression indicated notable differences in the access of the two AAV serotypes to primary afferent neurons via peripheral delivery in the colon and to spinal projections neurons via intracranial delivery within the parabrachial complex. Additionally, our results highlight the superior sensitivity of detection of neuronal transduction based on reporter expression relative to expression of viral products.

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“…Patients with neuropathic pain are heterogeneous in pathophysiology, etiology and clinical presentation (460). Neuropathic pain can result from sources as varied as nerve compression, channelopathy, autoimmune disease, infection, disease or chemotherapy-induced neuropathy and the response of each individual is determined by a multiplicity of factors such as inherited genetic variants, sex, neonatal injury or maternal separation, age, ethnicity, intestinal microbiome, personality variables, and environmental factors (444,(461)(462)(463)(464)(465)(466)(467).…”

Section: Think About Sexmentioning

confidence: 99%

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles

Smith

2021

Front. Pain Res.

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The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

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Neonatal Injury Evokes Persistent Deficits in Dynorphin Inhibitory Circuits within the Adult Mouse Superficial Dorsal Horn

Cited by 19 publications

References 66 publications

A harmonized atlas of mouse spinal cord cell types and their spatial organization

A harmonized atlas of mouse spinal cord cell types and their spatial organization

Targeting the somatosensory system with AAV9 and AAV2retro viral vectors

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

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