Highlights
- •Astrocytes in rACC contribute to the maintenance of stress-related VH.
- •Upregulated TSP1 and BDNF induced by astrocytic activation may mediate the effect of astrocytes on VH.
- •STAT1 is a downstream mediator of ERK signaling, resulting in VH via activating astrocytes.
Abstract
The rostral anterior cingulate cortex (rACC) has been found to be an important brain
region in mediating visceral hypersensitivity. However, the underlying mechanisms
remain unclear. This study aimed to explore the role of astrocytes in the maintenance
of visceral hypersensitivity induced by chronic water avoidance stress (WAS) as well
as the potential signaling pathway that activates astrocytes in the rACC. We found
that ACC-reactive astrogliosis resulted in the overexpression of c-fos, TSP-1, and
BDNF in stress-related visceral hypersensitivity rats. Visceral hypersensitivity was
reversed by pharmacological inhibition of astrocytic activation after WAS, as were
the overexpression of c-fos, TSP-1 and BDNF. Activation of the astrocytic Gi-pathway
increased the visceral sensitivity and expression of c-fos, TSP-1, and BDNF. Visceral
hypersensitivity was also ameliorated by the pharmacological inhibition of ERK and
STAT1 phosphorylation after WAS. Furthermore, inhibition of the ERK-STAT1 cascade
reduced astrocytic activation. These findings suggest that astrocytic ERK/STAT1 signaling
in the rACC contributes to the maintenance of stress-related visceral hypersensitivity.
Perspective
Visceral hypersensitivity is a key factor in the pathophysiology of irritable bowel
syndrome. This study highlights the important role of astrocytic ERK/STAT1 signaling
in activating astrocytes in the rostral anterior cingulate cortex, which contributes
to visceral hypersensitivity.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Contribution of astrocytes to neuropathology of neurodegenerative diseases.Brain Res. 2021; 1758147291
- Astrocyte-induced modulation of synaptic transmission.Can J Physiol Pharmacol. 1999; 77: 699-706
- Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain.J Neurosci. 2009; 29: 3307-3321
- Anterior cingulate cortex modulates visceral pain as measured by visceromotor responses in viscerally hypersensitive rats.Gastroenterology. 2008; 134: 535-543
- The role of ERK1/2 in the regulation of proliferation and differentiation of astrocytes in developing brain.Int J Dev Neurosci. 2013; 31: 783-789
- Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.Cell. 2005; 120: 421-433
- Arundic acid (ONO-2506), an Inhibitor of S100B protein synthesis, prevents neurological deficits and brain tissue damage following intracerebral hemorrhage in male wistar rats.Neuroscience. 2020; 440: 97-112
- STAT1/3 and ERK1/2 synergistically regulate cardiac fibrosis induced by high glucose.Cell Physiol Biochem. 2013; 32: 960-971
- Biphasic activation of extracellular signal-regulated kinase in anterior cingulate cortex distinctly regulates the development of pain-related anxiety and mechanical hypersensitivity in rats after incision.Anesthesiology. 2011; 115: 604-613
- Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission.Glia. 2019; 67: 1076-1093
- The role of astrocyte-secreted matricellular proteins in central nervous system development and function.J Cell Commun Signal. 2009; 3: 167-176
- Regulation of synaptic connectivity by glia.Nature. 2010; 468: 223-231
- The roles of cortical astrocytes in chronic pain and other brain pathologies.Neurosci Res. 2018; 126: 3-8
- Astrocytic propagation of tau in the context of Alzheimer's disease.Front Cell Neurosci. 2021; 15645233
- Targeting astrocyte signaling for chronic pain.Neurotherapeutics. 2010; 7: 482-493
- Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways.Glia. 2011; 59: 242-255
- A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis.Nat Neurosci. 2005; 8: 616-625
- NADPH oxidase-derived H2O2 mediates the regulatory effects of microglia on astrogliosis in experimental models of Parkinson's disease.Redox Biol. 2017; 12: 162-170
- Elucidating the putative link between prefrontal neurotransmission, functional connectivity, and affective symptoms in irritable bowel syndrome.Sci Rep. 2019; 9: 13590
- Pain regulation by non-neuronal cells and inflammation.Science. 2016; 354: 572-577
- Abnormal regional homogeneity in patients with irritable bowel syndrome: A resting-state functional MRI study.Neuro gastroenterol Motil. 2015; 27: 1796-1803
- Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain.J Clin Invest. 2016; 126: 1983-1997
- Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder.Pain. 2011; 152: 2117-2124
- Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells.Glia. 2005; 50: 66-79
- Astrocyte secretes IL-6 to modulate PSD-95 palmitoylation in basolateral amygdala and depression-like behaviors induced by peripheral nerve injury.Brain Behav Immun. 2022; 104: 139-154
- Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice.PeerJ. 2015; 3: e1350
- Clinical practice. Irritable bowel syndrome.N Engl J Med. 2008; 358: 1692-1699
- Neuron-Astrocyte Interactions in Parkinson's Disease.Cells. 2020; 9
- STAT3 as a downstream mediator of Trk signaling and functions.J Biol Chem. 2006; 281: 15636-15644
- Neurotrophin regulation of neural circuit development and function.Nat Rev Neurosci. 2013; 14: 7-23
- Activation of extracellular signal-regulated kinase1/2 in the medial prefrontal cortex contributes to stress-induced hyperalgesia.Mol Neurobiol. 2014; 50: 1013-1023
- Thrombospondins as key regulators of synaptogenesis in the central nervous system.Matrix Biol. 2012; 31: 170-177
- Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine.Sci Adv. 2020; 6: eaaz1584
- Visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: consistent findings from five different patient cohorts.Gut. 2018; 67: 255-262
- Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats.Acta Pharmacol Sin. 2005; 26: 789-798
- STAT1 as a downstream mediator of ERK signaling contributes to bone cancer pain by regulating MHC II expression in spinal microglia.Brain Behav Immun. 2017; 60: 161-173
- Role of neurotrophins in central synapse formation and stabilization.Nat Rev Neurosci. 2002; 3: 965-974
- Magnetic resonance imaging analysis of brain function in patients with irritable bowel syndrome.BMC Gastroenterol. 2017; 17: 148
- A novel progress: Glial cells and inflammatory pain.ACS Chem Neurosci. 2022; 13: 288-295
- Astrocytic l-Lactate signaling facilitates amygdala-anterior cingulate cortex synchrony and decision making in rats.Cell Rep. 2017; 21: 2407-2418
- Astrocyte-neuron lactate transport in the ACC contributes to the occurrence of long-lasting inflammatory pain in male mice.Neurosci Lett. 2021; 764136205
- Calcitonin gene-related peptide as a regulator of neuronal CaMKII-CREB, microglial p38-NFkappaB and astroglial ERK-Stat1/3 cascades mediating the development of tolerance to morphine-induced analgesia.Pain. 2010; 151: 194-205
- Down-regulation of HTR1A-modulated ACC activation contributes to stress-induced visceral hyperalgesia in rats.Neurogastroenterol Motil. 2019; 31: e13620
- Dystroglycan is involved in the activation of ERK pathway inducing the change of AQP4 expression in scratch-injured astrocytes.Brain Res. 2019; 1721146347
- Electroacupuncture Inhibits the activity of astrocytes in spinal cord in rats with visceral hypersensitivity by inhibiting P2Y1 Receptor-Mediated MAPK/ERK Signaling Pathway.Evid Based Complement Alternat Med. 2020; 20204956179
- Electroacupuncture improves IBS visceral hypersensitivity by inhibiting the activation of astrocytes in the medial thalamus and anterior cingulate cortex.Evid Based Complement Alternat Med. 2020; 20202562979
- Extracellular signal-regulated kinase activation in the spinal cord contributes to visceral hypersensitivity induced by craniofacial injury followed by stress.Neurogastroenterol Motil. 2018; 30e13161https://doi.org/10.1111/nmo.13161
- ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.Pain. 2005; 114: 149-159
Article Info
Publication History
Published online: July 28, 2022
Accepted:
July 20,
2022
Received in revised form:
July 19,
2022
Received:
November 25,
2021
Footnotes
Conflict of interest statement: This work was supported by National Natural Science Foundation of China (grant No. 81974067 ), Shanghai Informatization Development Special project ( 202001003 ), Psychosomatic Medicine Project of Key Developing Disciplines of Shanghai Municipal Health Commission ( 2019ZB0202 ). We declared that there was no conflict of interest in this study.
Identification
Copyright
© 2022 by United States Association for the Study of Pain, Inc.
