Repetitive and compulsive behavior after Early-Life-Pain associated with reduced long-chain sphingolipid species.

Calcium Compulsive behavior Cortical excitability IntelliCage Multichannel electrode arrays Nociception Optogenetic Repetitiveness

Journal

Cell & bioscience
ISSN: 2045-3701
Titre abrégé: Cell Biosci
Pays: England
ID NLM: 101561195

Informations de publication

Date de publication:
27 Aug 2023
Historique:
received: 04 04 2023
accepted: 13 08 2023
medline: 28 8 2023
pubmed: 28 8 2023
entrez: 27 8 2023
Statut: epublish

Résumé

Pain in early life may impact on development and risk of chronic pain. We developed an optogenetic Cre/loxP mouse model of "early-life-pain" (ELP) using mice with transgenic expression of channelrhodopsin-2 (ChR2) under control of the Advillin (Avil) promoter, which drives expression of transgenes predominantly in isolectin B4 positive non-peptidergic nociceptors in postnatal mice. Avil-ChR2 (Cre +) and ChR2-flfl control mice were exposed to blue light in a chamber once daily from P1-P5 together with their Cre-negative mother. ELP caused cortical hyperexcitability at P8-9 as assessed via multi-electrode array recordings that coincided with reduced expression of synaptic genes (RNAseq) including Grin2b, neurexins, piccolo and voltage gated calcium and sodium channels. Young adult (8-16 wks) Avil-ChR2 mice presented with nociceptive hypersensitivity upon heat or mechanical stimulation, which did not resolve up until one year of age. The persistent hypersensitivy to nociceptive stimuli was reflected by increased calcium fluxes in primary sensory neurons of aged mice (1 year) upon capsaicin stimulation. Avil-ChR2 mice behaved like controls in maze tests of anxiety, social interaction, and spatial memory but IntelliCage behavioral studies revealed repetitive nosepokes and corner visits and compulsive lickings. Compulsiveness at the behavioral level was associated with a reduction of sphingomyelin species in brain and plasma lipidomic studies. Behavioral studies were done with female mice. The results suggest that ELP may predispose to chronic "pain" and compulsive psychopathology in part mediated by alterations of sphingolipid metabolism, which have been previously described in the context of addiction and psychiatric diseases.

Sections du résumé

BACKGROUND BACKGROUND
Pain in early life may impact on development and risk of chronic pain. We developed an optogenetic Cre/loxP mouse model of "early-life-pain" (ELP) using mice with transgenic expression of channelrhodopsin-2 (ChR2) under control of the Advillin (Avil) promoter, which drives expression of transgenes predominantly in isolectin B4 positive non-peptidergic nociceptors in postnatal mice. Avil-ChR2 (Cre +) and ChR2-flfl control mice were exposed to blue light in a chamber once daily from P1-P5 together with their Cre-negative mother.
RESULTS RESULTS
ELP caused cortical hyperexcitability at P8-9 as assessed via multi-electrode array recordings that coincided with reduced expression of synaptic genes (RNAseq) including Grin2b, neurexins, piccolo and voltage gated calcium and sodium channels. Young adult (8-16 wks) Avil-ChR2 mice presented with nociceptive hypersensitivity upon heat or mechanical stimulation, which did not resolve up until one year of age. The persistent hypersensitivy to nociceptive stimuli was reflected by increased calcium fluxes in primary sensory neurons of aged mice (1 year) upon capsaicin stimulation. Avil-ChR2 mice behaved like controls in maze tests of anxiety, social interaction, and spatial memory but IntelliCage behavioral studies revealed repetitive nosepokes and corner visits and compulsive lickings. Compulsiveness at the behavioral level was associated with a reduction of sphingomyelin species in brain and plasma lipidomic studies. Behavioral studies were done with female mice.
CONCLUSION CONCLUSIONS
The results suggest that ELP may predispose to chronic "pain" and compulsive psychopathology in part mediated by alterations of sphingolipid metabolism, which have been previously described in the context of addiction and psychiatric diseases.

Identifiants

pubmed: 37635256
doi: 10.1186/s13578-023-01106-3
pii: 10.1186/s13578-023-01106-3
pmc: PMC10463951
doi:

Types de publication

Journal Article

Langues

eng

Pagination

155

Subventions

Organisme : Deutsche Forschungsgemeinschaft
ID : CRC1039 A03
Organisme : Deutsche Forschungsgemeinschaft
ID : CRC1080 C02
Organisme : Deutsche Forschungsgemeinschaft
ID : CRC1080 C02
Organisme : Deutsche Forschungsgemeinschaft
ID : CRC1039 Z01
Organisme : Deutsche Forschungsgemeinschaft
ID : 445757098

Informations de copyright

© 2023. Society of Chinese Bioscientists in America (SCBA).

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Auteurs

Alexandra Vogel (A)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.

Timo Ueberbach (T)

Institute of Physiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Annett Wilken-Schmitz (A)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.

Lisa Hahnefeld (L)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596, Frankfurt, Germany.
Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), 60596, Frankfurt, Germany.

Luisa Franck (L)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.

Marc-Philipp Weyer (MP)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.

Tassilo Jungenitz (T)

Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt, Germany.

Tobias Schmid (T)

Institute of Biochemistry I, Faculty of Medicine, Goethe-University, Frankfurt, Germany.
Partner Site Frankfurt, German Cancer Consortium (DKTK), Frankfurt, Germany.

Giulia Buchmann (G)

Institute of Cardiovascular Physiology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.

Florian Freudenberg (F)

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University Hospital, Frankfurt, Germany.

Ralf P Brandes (RP)

Institute of Cardiovascular Physiology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.

Robert Gurke (R)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596, Frankfurt, Germany.
Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), 60596, Frankfurt, Germany.

Stephan W Schwarzacher (SW)

Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt, Germany.

Gerd Geisslinger (G)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596, Frankfurt, Germany.
Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), 60596, Frankfurt, Germany.

Thomas Mittmann (T)

Institute of Physiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Irmgard Tegeder (I)

Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University, Frankfurt, Germany. itegeder@hotmail.com.

Classifications MeSH