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Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain
- Source :
- PLoS ONE, Vol 17, Iss 1 (2022), PLoS ONE, Vol 17, Iss 1, p e0262769 (2022), PLoS ONE
- Publication Year :
- 2022
- Publisher :
- Public Library of Science (PLoS), 2022.
-
Abstract
- The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization in vivo in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGFA) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGFA-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGFA-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of TRPV1-Cre-ZGreen mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (i. p.) in awake animals to silence TRPV1 expressing sensory neurons in vivo during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGFA in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGFA instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGFA-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons in vivo completely reversed VEGFA-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients.
- Subjects :
- Male
Vascular Endothelial Growth Factor A
Cell signaling
Muscle Physiology
Physiology
Social Sciences
Fluorescent Antibody Technique
Signal transduction
Mice
Animal Cells
Medicine and Health Sciences
Psychology
Neurons
Analgesics
Multidisciplinary
Pain Perception
Animal Models
VEGF signaling
Experimental Organism Systems
Medicine
Sensory Perception
Female
Anatomy
Cellular Types
Chronic Pain
Research Article
Muscle Contraction
Sensory Receptor Cells
Bladder
Science
Immunology
Mouse Models
Mice, Transgenic
Research and Analysis Methods
Pelvic Pain
Real-Time Polymerase Chain Reaction
Model Organisms
Hypersensitivity
Animals
Cognitive Psychology
Lumbosacral Region
Biology and Life Sciences
Renal System
Cell Biology
Mice, Inbred C57BL
Disease Models, Animal
Cellular Neuroscience
Animal Studies
Cognitive Science
Sensory Neurons
Clinical Immunology
Perception
Clinical Medicine
Neuroscience
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....e1cdc8f2d6dc937d9069689fada6cec5
- Full Text :
- https://doi.org/10.1371/journal.pone.0262769