21 results on '"Kerri D. Pryce"'
Search Results
2. SARS-CoV-2 airway infection results in the development of somatosensory abnormalities in a hamster model
- Author
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Randal A. Serafini, Justin J. Frere, Jeffrey Zimering, Ilinca M. Giosan, Kerri D. Pryce, Ilona Golynker, Maryline Panis, Anne Ruiz, Benjamin R. tenOever, and Venetia Zachariou
- Subjects
Cell Biology ,Molecular Biology ,Biochemistry - Abstract
Although largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and chronic phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster model to characterize and compare the effects of infection with SARS-CoV-2 and influenza A virus (IAV) on the sensory nervous system. We detected SARS-CoV-2 transcripts but no infectious material in the cervical and thoracic spinal cord and dorsal root ganglia (DRGs) within the first 24 hours of intranasal virus infection. SARS-CoV-2–infected hamsters exhibited mechanical hypersensitivity that was milder but prolonged compared with that observed in IAV-infected hamsters. RNA sequencing analysis of thoracic DRGs 1 to 4 days after infection suggested perturbations in predominantly neuronal signaling in SARS-CoV-2–infected animals as opposed to type I interferon signaling in IAV-infected animals. Later, 31 days after infection, a neuropathic transcriptome emerged in thoracic DRGs from SARS-CoV-2–infected animals, which coincided with SARS-CoV-2–specific mechanical hypersensitivity. These data revealed potential targets for pain management, including the RNA binding protein ILF3, which was validated in murine pain models. This work elucidates transcriptomic signatures in the DRGs triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities.
- Published
- 2023
3. SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model
- Author
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Randal A. Serafini, Justin J. Frere, Jeffrey Zimering, Ilinca M. Giosan, Kerri D. Pryce, Ilona Golynker, Maryline Panis, Anne Ruiz, Benjamin tenOever, and Venetia Zachariou
- Abstract
Despite being largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and long-lasting phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster infection model to characterize the effects of SARS-CoV-2 versus Influenza A virus (IAV) infection on the sensory nervous system. Efforts to detect the presence of virus in the cervical/thoracic spinal cord and dorsal root ganglia (DRGs) demonstrated detectable levels of SARS-CoV-2 by quantitative PCR and RNAscope uniquely within the first 24 hours of infection. SARS-CoV-2-infected hamsters demonstrated mechanical hypersensitivity during acute infection; intriguingly, this hypersensitivity was milder, but prolonged when compared to IAV-infected hamsters. RNA sequencing (RNA-seq) of thoracic DRGs from acute infection revealed predominantly neuron-biased signaling perturbations in SARS-CoV-2-infected animals as opposed to type I interferon signaling in tissue derived from IAV-infected animals. RNA-seq of 31dpi thoracic DRGs from SARS-CoV-2-infected animals highlighted a uniquely neuropathic transcriptomic landscape, which was consistent with substantial SARS-CoV-2-specific mechanical hypersensitivity at 28dpi. Ontology analysis of 1, 4, and 30dpi RNA-seq revealed novel targets for pain management, such as ILF3. Meta-analysis of all SARS-CoV-2 RNA-seq timepoints against preclinical pain model datasets highlighted both conserved and unique pro-nociceptive gene expression changes following infection. Overall, this work elucidates novel transcriptomic signatures triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities while also highlighting several therapeutic targets for alleviation of infection-induced hypersensitivity.One Sentence SummarySARS-CoV-2 infection results in an interferon-associated transcriptional response in sensory tissues underlying time-dependent hypersensitivity.
- Published
- 2022
4. A novel HDAC1/2 inhibitor alleviates physical and emotional symptoms associated with spontaneous oxycodone withdrawal in neuropathic pain mice
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Kerri D. Pryce, Aarthi Ramakrishnan, Hope Kronnman, Andrew Nicolais, Claire Polizu, Anne Ruiz, Randal Serafini, Sevasti Gaspari, Catherine J. Pena, Angelica Torres‐Berrio, Vassiliki Mitsi, Matthew Darpe, LI Shen, Eric J. Nestler, and Venetia Zachariou
- Subjects
Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
5. Targeting HDAC6 in the Dorsal Root Ganglia Attenuates Peripheral Nerve Injury‐induced Hypersensitivity
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Ilinca M. Giosan, Jeffery Zimering, Randal A. Serafini, Kerri D. Pryce, and Venetia Zachariou
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
6. A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward
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Farhana Sakloth, Omar B. Sanchez-Reyes, Anne Ruiz, Andrew Nicolais, Randal A. Serafini, Kerri D. Pryce, Feodora Bertherat, Angélica Torres-Berrío, Ivone Gomes, Lakshmi A. Devi, Daniel Wacker, and Venetia Zachariou
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Pharmacology ,Analgesics, Opioid ,Mice ,Morphine ,Reward ,GTP-Binding Proteins ,Receptors, Opioid, mu ,Molecular Medicine ,Animals ,Periaqueductal Gray ,Signal Transduction - Abstract
Opioid analgesics exert their therapeutic and adverse effects by activating
- Published
- 2022
7. SARS-CoV-2 infection results in lasting and systemic perturbations post recovery
- Author
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Justin J. Frere, Randal A. Serafini, Kerri D. Pryce, Marianna Zazhytska, Kohei Oishi, Ilona Golynker, Maryline Panis, Jeffrey Zimering, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Jonathan B. Overdevest, Albana Kodra, Peter D. Canoll, James E. Goldman, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, and Benjamin R. tenOever
- Abstract
SUMMARYSARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.
- Published
- 2022
8. The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities
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Venetia Zachariou, Randal A. Serafini, and Kerri D. Pryce
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0301 basic medicine ,Dopamine ,media_common.quotation_subject ,Affect (psychology) ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neurochemical ,Reward ,Humans ,Medicine ,Biological Psychiatry ,Depression (differential diagnoses) ,media_common ,business.industry ,Addiction ,Chronic pain ,Brain ,medicine.disease ,Behavior, Addictive ,030104 developmental biology ,Mood disorders ,Brain stimulation reward ,Chronic Pain ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Chronic pain is a complex neuropsychiatric disorder, characterized by sensory, cognitive, and affective symptoms. Over the last two decades, researchers have made significant progress towards understanding the impact of mesolimbic dopamine circuitry in acute and chronic pain. These efforts have provided insights into the circuits and intracellular pathways in the brain reward center that are implicated in sensory and affective manifestations of chronic pain. Studies have also identified novel therapeutic targets as well as factors that impact treatment responsiveness. Dysregulation of dopamine function in the brain reward center may further promote comorbid mood disorders and vulnerability to addiction. This review discusses recent clinical and preclinical findings on the neuroanatomical and neurochemical adaptations triggered by prolonged pain states in the brain reward pathway. Furthermore, this discussion highlights evidence of mechanisms underlying comorbidities between pain, depression, and addiction.
- Published
- 2020
9. Chronic pain‐mediated Regulator of G protein signaling 4 (RGS4) gene expression in superficial dorsal horn of spinal cord
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Jeffrey Zimering, Kerri D. Pryce, and Venetia Zachariou
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Dorsum ,French horn ,Chronic pain ,Biology ,Spinal cord ,medicine.disease ,Biochemistry ,Cell biology ,medicine.anatomical_structure ,Regulator of G protein signaling ,Rgs4 gene ,Genetics ,medicine ,Molecular Biology ,Biotechnology - Published
- 2021
10. Magi‐1 scaffolds Na v 1‐8 and Slack K Na channels in dorsal root ganglion neurons regulating excitability and pain
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Danielle L. Tomasello, Garrett D. Sheehan, Arin Bhattacharjee, Rasheen Powell, Katherine M. Evely, Kerri D. Pryce, Allan Nip, Sushmitha Gururaj, and Dalia Agwa
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Nociception ,0301 basic medicine ,Scaffold protein ,Sensory Receptor Cells ,Guanylate kinase ,PDZ Domains ,Nerve Tissue Proteins ,Potassium Channels, Sodium-Activated ,Biochemistry ,Injections ,NAV1.8 Voltage-Gated Sodium Channel ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Dorsal root ganglion ,Postsynaptic potential ,Ganglia, Spinal ,Protein Interaction Mapping ,Ranvier's Nodes ,Genetics ,medicine ,Animals ,Amino Acid Sequence ,RNA, Small Interfering ,Molecular Biology ,Cells, Cultured ,Ion transporter ,Sequence Homology, Amino Acid ,Chemistry ,Research ,Sodium channel ,Membrane Proteins ,Axons ,Potassium channel ,Rats ,Cell biology ,Spinal Nerves ,030104 developmental biology ,medicine.anatomical_structure ,NAV1 ,Female ,Guanylate Kinases ,Sequence Alignment ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Voltage-dependent sodium (Na(V)) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that Na(V)1.8 channel plasma membrane localization, retention, and stability occur through a direct interaction with the postsynaptic density-95/discs large/zonula occludens-1–and WW domain–containing scaffold protein called membrane-associated guanylate kinase with inverted orientation (Magi)-1. The neurophysiological roles of Magi-1 are largely unknown, but we found that dorsal root ganglion (DRG)–specific knockdown of Magi-1 attenuated thermal nociception and acute inflammatory pain and produced deficits in Na(V)1.8 protein expression. A competing cell-penetrating peptide mimetic derived from the Na(V)1.8 WW binding motif decreased sodium currents, reduced Na(V)1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in Na(V)1.8 surface expression and repetitive firing. Likewise, in vivo, the peptides produced diverging effects on nocifensive behavior. Additionally, we found that Magi-1 bound to sequence like a calcium-activated potassium channel sodium-activated (Slack) potassium channels, demonstrating macrocomplexing with Na(V)1.8 channels. Taken together, these findings emphasize Magi-1 as an essential scaffold for ion transport in DRG neurons and a central player in pain.—Pryce, K. D., Powell, R., Agwa, D., Evely, K. M., Sheehan, G. D., Nip, A., Tomasello, D. L., Gururaj, S., Bhattacharjee, A. Magi-1 scaffolds Na(V)1.8 and Slack K(Na) channels in dorsal root ganglion neurons regulating excitability and pain.
- Published
- 2019
11. A Molecular Basis of Long COVID-19
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Shu Horiuchi, Yaron Bram, Venetia Zachariou, Rasmus Moeller, Maryline Panis, Jiwoon Park, Christopher E. Mason, Jeffrey Zimering, Justin J. Frere, Kohei Oishi, Ilona Golynker, Jonathan Foox, Randal A. Serafini, Alain C. Borczuk, Daisy A. Hoagland, Cem Meydan, Benjamin R. tenOever, Kerri D. Pryce, Vasuretha Chandar, Anne Ruiz, and Robert E. Schwartz
- Subjects
medicine.medical_specialty ,Research use ,Coronavirus disease 2019 (COVID-19) ,Next of kin ,business.industry ,Approved Protocol ,Health Insurance Portability and Accountability Act ,Emergency medicine ,Pandemic ,medicine ,business ,Institutional review board ,Tissue procurement - Abstract
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found capable of inducing long term effects commonly referred to as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. To define the molecular basis of this condition, we compared the short- and long-term responses to influenza A virus and SARSCoV-2 in the golden hamster model. These data demonstrated that SARS-CoV-2 resulted in sustained changes to lung, kidney, and brain. The most significant change in response to SARS-CoV-2 was observed in the olfactory bulb, where persistent inflammation was visible beyond one month post infection. This was characterized by microglial activation, pro-inflammatory cytokine production, and a Type I interferon (IFN-I) response in the absence of detectable virus. Given the connection between olfactory bulb injury and neurological disorders, we postulate that this prolonged inflammation is an underlying cause of long COVID. Funding Information: This work was funded by generous support from the Marc Haas Foundation, the National Institutes of Health (NCI (R01CA234614) and NIAID (2R01AI107301) and NIDDK (R01DK121072 and 1RO3DK117252) to Department of Medicine, Weill Cornell Medicine (R.E.S.)), and DARPA’s PREPARE Program (HR0011-20-2-0040). The work was further funded by NINDS (NS111251, NSO86444, NSO86444S1)(V.Z., R.A.S.). Ethics Approval Statement: The Tissue Procurement Facility operates under Institutional Review Board (IRB) approved protocol and follows guidelines set by Health Insurance Portability and Accountability Act (HIPAA). Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the IRB at the Weill Cornell Medicine. The autopsy samples are considered human tissue research and were collected under IRB protocols 20-04021814 and 19-11021069. All autopsies have consent for research use from next of kin, and these studies were determined as exempt by IRB at Weill Cornell Medicine under those protocol numbers.
- Published
- 2021
12. HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice
- Author
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Kerri D. Pryce, Kleopatra Avrampou, Lefteris Manouras, Valeria Cogliani, Vasiliki Mitsi, Venetia Zachariou, Olivier Berton, Farhana Sakloth, Randal A. Serafini, and Matthew Jarpe
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Male ,SNi ,Inflammation ,Pharmacology ,Histone Deacetylase 6 ,Hydroxamic Acids ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Pain Measurement ,business.industry ,HDAC6 ,Nerve injury ,030227 psychiatry ,Peripheral ,Rats ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Nociception ,Pyrimidines ,Hyperalgesia ,Neuropathic pain ,Peripheral nerve injury ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
BACKGROUND: HDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation. METHODS: We utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund’s Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia. RESULTS: Using the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation. CONCLUSIONS: Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.
- Published
- 2020
13. RGS4 Maintains Chronic Pain Symptoms in Rodent Models
- Author
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Li Shen, Sevasti Gaspari, Barbara Ligas, Aarthi Ramakrishnan, Vasiliki Mitsi, Claire Polizu, Kerri D. Pryce, Cole Swartz, Randal A. Serafini, Kleopatra Avrampou, Fiona B. Carr, Venetia Zachariou, Farhana Sakloth, and Abigail Richards
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0301 basic medicine ,Male ,Down-Regulation ,Inflammation ,RGS4 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Sex Factors ,medicine ,Animals ,Research Articles ,Pain Measurement ,Mice, Knockout ,biology ,business.industry ,General Neuroscience ,Chronic pain ,Nerve injury ,medicine.disease ,030104 developmental biology ,Allodynia ,Hyperalgesia ,Thalamic Nuclei ,Neuropathic pain ,biology.protein ,Female ,medicine.symptom ,Metabotropic glutamate receptor 2 ,Signal transduction ,Chronic Pain ,business ,Neuroscience ,030217 neurology & neurosurgery ,RGS Proteins ,Signal Transduction - Abstract
Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and female mice. Using paradigms of peripheral inflammation and nerve injury, we show that the prevention of RGS4 action leads to recovery from mechanical and cold allodynia and increases the motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's Adjuvant (CFA) model of hindpaw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity pathway analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, Western blot analysis shows increased expression of metabotropic glutamate receptor 2 in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target.SIGNIFICANCE STATEMENTThere is an imminent need for safe and efficient chronic pain medications. Regulator of G-protein signaling 4 (RGS4) is a multifunctional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominent role in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice, we show a dynamic role of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hindpaw inflammation or hindlimb nerve injury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in the mouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states and demonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.
- Published
- 2019
14. Protein kinase A–induced internalization of Slack channels from the neuronal membrane occurs by adaptor protein-2/clathrin–mediated endocytosis
- Author
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Jun Qu, Jun Li, Katherine M. Evely, Kerri D. Pryce, Arin Bhattacharjee, and Sushmitha Gururaj
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0301 basic medicine ,Potassium Channels ,Nerve Tissue Proteins ,Potassium Channels, Sodium-Activated ,Endocytosis ,Biochemistry ,Clathrin ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Neurobiology ,Dorsal root ganglion ,Ganglia, Spinal ,medicine ,Animals ,Molecular Biology ,Cells, Cultured ,Neurons ,biology ,Cell Membrane ,Signal transducing adaptor protein ,Cell Biology ,Anatomy ,Receptor-mediated endocytosis ,Cyclic AMP-Dependent Protein Kinases ,Potassium channel ,Rats ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Transcription Factor AP-2 ,nervous system ,biology.protein ,Membrane channel ,Female ,Neuron ,030217 neurology & neurosurgery - Abstract
The sodium-activated potassium (KNa) channel Kcnt1 (Slack) is abundantly expressed in nociceptor (pain-sensing) neurons of the dorsal root ganglion (DRG), where they transmit the large outward conductance IKNa and arbitrate membrane excitability. Slack channel expression at the DRG membrane is necessary for their characteristic firing accommodation during maintained stimulation, and reduced membrane channel density causes hyperexcitability. We have previously shown that in a pro-inflammatory state, a decrease in membrane channel expression leading to reduced Slack-mediated IKNa expression underlies DRG neuronal sensitization. An important component of the inflammatory milieu, PKA internalizes Slack channels from the DRG membrane, reduces IKNa, and produces DRG neuronal hyperexcitability when activated in cultured primary DRG neurons. Here, we show that this PKA-induced retrograde trafficking of Slack channels also occurs in intact spinal cord slices and that it is carried out by adaptor protein-2 (AP-2) via clathrin-mediated endocytosis. We provide mass spectrometric and biochemical evidence of an association of native neuronal AP-2 adaptor proteins with Slack channels, facilitated by a dileucine motif housed in the cytoplasmic Slack C terminus that binds AP-2. By creating a competitive peptide blocker of AP-2–Slack binding, we demonstrated that this interaction is essential for clathrin recruitment to the DRG membrane, Slack channel endocytosis, and DRG neuronal hyperexcitability after PKA activation. Together, these findings uncover AP-2 and clathrin as players in Slack channel regulation. Given the significant role of Slack in nociceptive neuronal excitability, the AP-2 clathrin–mediated endocytosis trafficking mechanism may enable targeting of peripheral and possibly, central neuronal sensitization.
- Published
- 2017
15. A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects
- Author
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Feodora Bertherat, Bryan L. Roth, Tao Che, K. Toth, Kerri D. Pryce, H. U. Kaniskan, Michael D. Cameron, Jian Jin, Yun Liu, Abhijeet Kapoor, L. Qin, Marta Filizola, Venetia Zachariou, Farhana Sakloth, A. Nicolais, Susan Khan, and Hye Jin Kang
- Subjects
Male ,Nociception ,Pain Threshold ,0301 basic medicine ,medicine.drug_class ,Analgesic ,Receptors, Opioid, mu ,Pain ,Pharmacology ,Article ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Allosteric Regulation ,Opioid receptor ,In vivo ,medicine ,Animals ,Adverse effect ,Pain Measurement ,Analgesics ,business.industry ,030104 developmental biology ,Opioid ,Morphine ,Female ,business ,Oxycodone ,030217 neurology & neurosurgery ,Methadone ,medicine.drug - Abstract
Positive allosteric modulators (PAMs) of the µ-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.
- Published
- 2021
16. Targeting RGSz1 actions in the periaqueductal gray promotes opioid analgesia and decreases reward sensitivity
- Author
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Kerri D. Pryce, Farhana Sakloth, Mandakini B. Singh, Sevasti Gaspari, and Venetia Zachariou
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Opioid ,Reward sensitivity ,business.industry ,Genetics ,Medicine ,business ,Molecular Biology ,Biochemistry ,Periaqueductal gray ,Neuroscience ,Biotechnology ,medicine.drug - Published
- 2019
17. Oxycodone‐induced gene expression adaptations in the brain reward center in a murine model of neuropathic pain
- Author
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Claire Polizu, Kerri D. Pryce, Angélica Torres-Berrío, Li Shen, Hope Kronman, Aarthi Ramakrishnan, Venetia Zachariou, Eric J. Nestler, and Catherine Jensen Pena
- Subjects
business.industry ,Biochemistry ,Murine model ,Neuropathic pain ,Gene expression ,Genetics ,Medicine ,Brain stimulation reward ,Center (algebra and category theory) ,business ,Molecular Biology ,Oxycodone ,Neuroscience ,Biotechnology ,medicine.drug - Published
- 2019
18. Oxycodone‐induced Gene adaptations in the brain reward center in a murine Model of Neuropathic pain
- Author
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Kerri D. Pryce, Hope Kronman, Aarthi Ramakrishnan, Angelica Torres-Berrio, Claire D. Polizu, Catherine Pena, Li D. Shen, Eric Nestler, and Venetia Zachariou
- Subjects
Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2020
19. Slack KNa channels influence dorsal horn synapses and nociceptive behavior
- Author
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Samir Haj-Dahmane, Peter Ruth, Arin Bhattacharjee, Anne E. Bausch, Kerri D. Pryce, Robert Lukowski, and Katherine M. Evely
- Subjects
0301 basic medicine ,Dorsum ,Spinal Cord Dorsal Horn ,Potassium Channels ,Neuronal firing ,slice physiology ,Pain ,Nerve Tissue Proteins ,Neurotransmission ,Potassium Channels, Sodium-Activated ,Synaptic Transmission ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Dorsal root ganglion ,Ganglia, Spinal ,medicine ,Animals ,Mice, Knockout ,Afferent Pathways ,Chemistry ,Extramural ,musculoskeletal, neural, and ocular physiology ,spinal cord ,Nociceptors ,Spinal cord ,Potassium channel ,Electric Stimulation ,Posterior Horn Cells ,030104 developmental biology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Nociception ,thermal hyperalgesia ,nervous system ,Synapses ,Molecular Medicine ,Neuroscience ,030217 neurology & neurosurgery ,Research Article - Abstract
The sodium-activated potassium channel Slack (Kcnt1, Slo2.2) is highly expressed in dorsal root ganglion neurons where it regulates neuronal firing. Several studies have implicated the Slack channel in pain processing, but the precise mechanism or the levels within the sensory pathway where channels are involved remain unclear. Here, we furthered the behavioral characterization of Slack channel knockout mice and for the first time examined the role of Slack channels in the superficial, pain-processing lamina of the dorsal horn. We performed whole-cell recordings from spinal cord slices to examine the intrinsic and synaptic properties of putative inhibitory and excitatory lamina II interneurons. Slack channel deletion altered intrinsic properties and synaptic drive to favor an overall enhanced excitatory tone. We measured the amplitudes and paired pulse ratio of paired excitatory post-synaptic currents at primary afferent synapses evoked by electrical stimulation of the dorsal root entry zone. We found a substantial decrease in the paired pulse ratio at synapses in Slack deleted neurons compared to wildtype, indicating increased presynaptic release from primary afferents. Corroborating these data, plantar test showed Slack knockout mice have an enhanced nociceptive responsiveness to localized thermal stimuli compared to wildtype mice. Our findings suggest that Slack channels regulate synaptic transmission within the spinal cord dorsal horn and by doing so establishes the threshold for thermal nociception.
- Published
- 2017
20. The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype
- Author
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Arin Bhattacharjee, Kerri D. Pryce, and Katherine M. Evely
- Subjects
0301 basic medicine ,Ohtahara syndrome ,Potassium Channels ,Epilepsy, Frontal Lobe ,Mutant ,Autosomal dominant nocturnal frontal lobe epilepsy ,Nerve Tissue Proteins ,CHO Cells ,Biology ,Potassium Channels, Sodium-Activated ,medicine.disease_cause ,Article ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Cricetulus ,Mutant protein ,Leukoencephalopathies ,medicine ,Missense mutation ,Animals ,Genetics ,Mutation ,General Neuroscience ,Wild type ,medicine.disease ,Rats ,Disease Models, Animal ,030104 developmental biology ,Phenotype ,030217 neurology & neurosurgery - Abstract
Sodium-activated potassium (KNa) channels contribute to firing frequency adaptation and slow after hyperpolarization. The KCNT1 gene (also known as SLACK) encodes a KNa subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the SLACK C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Ohtahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016). An exome sequencing study identified a p.Phe932Ile KCNT1 mutation as the disease-causing change in a child with severe early infantile epileptic encephalopathy and abnormal myelination (Vanderver et al., 2014). We characterized an analogous mutation in the rat Slack channel and unexpectedly found this mutation to produce a loss-of-function phenotype. In an effort to restore current, we tested the known Slack channel opener loxapine. Loxapine exhibited no effect, indicating that this mutation either caused the channel to be insensitive to this established opener or proper translation and trafficking to the membrane was disrupted. Protein analysis confirmed that while total mutant protein did not differ from wild type, membrane expression of the mutant channel was substantially reduced. Although gain-of-function mutations to the Slack channel are linked to epileptic phenotypes, this is the first reported loss-of-function mutation linked to severe epilepsy and delayed myelination.
- Published
- 2016
21. Regulation of the sodium‐activated potassium channel Slack by MAGI‐1
- Author
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Kerri D. Pryce, Danielle L. Tomasello, Arin Bhattacharjee, and Dalia Agwa
- Subjects
Protein subunit ,Sodium ,Potassium ,chemistry.chemical_element ,Sensory system ,Biochemistry ,Potassium channel ,Cell biology ,nervous system ,chemistry ,Genetics ,Protein kinase A ,Molecular Biology ,Magi ,Biotechnology - Abstract
The sodium-activated potassium subunit Slack (Kcnt1) is highly expressed in sensory neurons and contributes to firing accommodation. Previous studies have shown that protein kinase A-induced intern...
- Published
- 2015
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