Role of Spinal Microglia in Visceral Hyperalgesia and NK1R Up-Regulation in a Rat Model of Chronic Stress
Open accessAbstract
Background & aims Chronic psychological stress is associated with visceral hyperalgesia and increased expression of spinal NK1 receptors (NK1Rs). We aimed to identify the role of spinal microglia in this process.Methods Male Wistar rats were exposed to water avoidance (WA) or sham stress 1 hour each day for 10 days and given daily injections of minocycline, the p38 inhibitor SB203580, or saline. Phosphorylation levels of the kinase p38 (P-p38), the microglia marker OX42, NK1R, and IkappaBalpha were assessed by immunoblotting and/or immunostaining of spinal samples collected at day 11. The visceromotor response to colorectal distention at baseline and following WA were also assayed in rats given injections of minocycline, SB203580, or vehicle. The effects of fractalkine were assessed on the visceromotor response in rats exposed to minocycline or vehicle.Results P-p38 protein levels and immunoreactivity were increased in stressed rats and colocalized with OX42-positive cells and neurons in the dorsal horn. This increase was reversed by minocycline or SB203580 exposure. Stress-induced increased NK1R expression was blocked by minocycline but not SB203580. WA-induced decreased IkappaBalpha expression was blocked by minocycline and SB203580. WA-induced hyperalgesia was blocked by minocycline and SB203580 intrathecally. Fractalkine-induced hyperalgesia was blocked by minocycline.Conclusions This is the first demonstration that stress-induced activation of spinal microglia has a key role in visceral hyperalgesia and associated spinal NK1R up-regulation.
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NK1R antagonism can mitigate alterations in the brain induced by chronic psychological stress, which is associated with visceral hypersensitivity and spinal NK1R up-regulation in female rodents and possibly in mice with induced endometriosis.
“Aside from delaying fibrogenesis, NK1R antagonism can also mitigate alterations in the brain induced by chronic psychological stress99–101, which is associated with visceral hypersensitivity and spinal NK1R up-regulation in female rodents102,103 and possibly in mouse with induced endometriosis as well104–106.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [103]
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- Authors
- Bradesi, S., Svensson, C. I., Steinauer, J., Pothoulakis, C., Yaksh, T. L., & Mayer, E. A.
- Affiliations
- University of California, Los Angeles (US)
- Karolinska Institutet (SE)
- University of California San Diego (US)
- Corresponding author
- Bradesi, Sylvie
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 136
- Issue
- 4
- Pages
- 1339-1348.e2
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2812027
- OpenAlex
- W2042924540
- Cited by
- 69
- References
- 45
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 6 · 2012: 5
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- GlaxoSmithKline
- Sanofi
- Danone
- National Institute on Drug Abuse (R01DA002110)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK033506, DK-48351, P01 DK-33506, R01DK048351, R01-DK47343, P50DK064539, P-50DK64539, R21DK071767, R01DK047343)
- National Institute of Neurological Disorders and Stroke (R01 NS16541, R01NS016541)
- National Center for Complementary and Integrative Health (R24 AT00281)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- spinal microglia, visceral hypersensitivity, chronic psychological stress, water avoidance stress, p38 MAPK, minocycline, SB203580, IκBα, fractalkine, visceromotor response, colorectal distension, dorsal horn, neuroinflammation
- MeSH terms
- Animals, Disease Models, Animal, Enzyme Inhibitors, Hyperalgesia, Imidazoles, Male, Minocycline, Pyridines, Spinal Nerves, Stress, Physiological, Viscera, Water Deprivation, Up-Regulation, Rats, Wistar, Microglia, Receptors, Neurokinin-1, p38 Mitogen-Activated Protein Kinases, Rats
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