Neonatal Maternal Deprivation Enhances Presynaptic P2X7 Receptor Transmission in Insular Cortex in an Adult Rat Model of Visceral Hypersensitivity

Zhang, Pingan; Xu, Qi-Ya; Lü, Xue; Zheng, Hongxing; Yan, Jun; Xiao, Ying; Xu, Guang–Yin

doi:10.1111/cns.12663

Cited by 20 publications

(20 citation statements)

References 47 publications

(68 reference statements)

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“…This implies that the acute stress causes visceral responses more often and earlier than somatic responses. Consistent with previous studies that stress led to colonic hypersensitivity 41,42 and functional dyspepsia-like gastric hypersensitivity in rats, 7 which was most likely mediated by stress hormones such as CORT and epinephrine, we demonstrated for the first time that CORT injection induced gastric hypersensitivity in normal rats. However, the detailed mechanisms of systematic application CORT are not well understood.…”

Section: Discussionsupporting

confidence: 91%

Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach

Lü

Wang

et al. 2017

J Neurogastroenterol Motil

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Background/AimsGastric hypersensitivity contributes to abdominal pain in patients with functional dyspepsia. Recent studies showed that hormones induced by stress are correlated with visceral hypersensitivity. However, the precise mechanisms underlying gastric hypersensitivity remain largely unknown. The aim of the present study was designed to investigate the roles of corticosterone (CORT) on excitability of dorsal root ganglion (DRG) neurons innervating the stomach. MethodsDRG neurons innervating the stomach were labeled by DiI injection into the stomach wall. Patch clamp recordings were employed to examine neural excitability and voltage-gated sodium channel currents. Electromyograph technique was used to determine the responses of neck muscles to gastric distension. ResultsIncubation of acutely isolated DRG neurons with CORT significantly depolarized action potential threshold and enhanced the number of action potentials induced by current stimulation of the neuron. Under voltage-clamp mode, incubation of CORT enhanced voltagegated sodium current density of the recorded neurons. Pre-incubation of GF109203X, an inhibitor of protein kinase C, blocked the CORT-induced hyperexcitability and potentiation of sodium currents. However, pre-incubation of H-89, an inhibitor of protein kinase A, did not alter the sodium current density. More importantly, intraperitoneal injection of CORT produced gastric hypersensitivity of healthy rats, which was blocked by pre-administration of GF109203X but not H-89. ConclusionsOur data strongly suggest that CORT rapidly enhanced neuronal excitability and sodium channel functions, which is most likely mediated by protein kinase C but not protein kinase A signaling pathway in DRG neurons innervating the stomach, thus underlying the gastric hypersensitivity induced by CORT injection.

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Section: Discussionsupporting

confidence: 91%

Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach

Lü

Wang

et al. 2017

J Neurogastroenterol Motil

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“…Chronic visceral hyperalgesia was induced by NMD and assessed by colorectal distension (CRD) threshold as described previously. 12 , 16 Experiments were performed in NMD rats at age of 6 to 7 weeks. The age-matched healthy male rats were used as control (CON).…”

Section: Methodsmentioning

confidence: 99%

“…Our recent report that neonatal maternal deprivation (NMD) enhances synaptic transmission by sensitization of P2X7Rs in right IC suggests an alteration of synapse plasticity in IC. 12 Studies from clinic perspective also provided several lines of evidence to strongly support an involvement of IC in chronic visceral hypersensitivity of patients with irritable bowel syndrome (IBS). Using a task-dependent functional magnetic resonance imaging technique to investigate the brain activity, two groups showed that hypersensitive patients with IBS had greater activation of insula and reduced deactivation in pregenual anterior cingulate cortex during noxious rectal distensions, compared to controls and normosensitive patients with IBS.…”

Section: Introductionmentioning

confidence: 99%

Sensitization of P2X3 receptors in insular cortex contributes to visceral pain of adult rats with neonatal maternal deprivation

Zhang

et al. 2018

Mol Pain

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AimsInsular cortex is a brain region critical for processing of the sensation. Purinergic receptors are involved in the formation of chronic pain. The aim of the present study was to explore the role and mechanism of P2X3 receptors (P2X3Rs) in insular cortex in chronic visceral pain.MethodsChronic visceral pain in adult rats was induced by neonatal maternal deprivation and measured by detecting the threshold of colorectal distension. Western blotting, immunofluorescence, and real-time quantitative polymerase chain reaction techniques were used to detect the expression and distribution of P2X3Rs. Synaptic transmission in insular cortex was recorded in brain slices by patch clamp techniques.ResultsExpression of P2X3Rs both at mRNA and protein levels in right hemisphere of insular cortex was significantly increased in neonatal maternal deprivation rats. In addition, P2X3Rs were expressed with NeuN or synaptophysin but not with glial fibrillary acidic protein and CD11b. The co-localization of P2X3Rs with NeuN or synaptophysin was greatly enhanced in right hemisphere of insular cortex in neonatal maternal deprivation rats. Furthermore, neonatal maternal deprivation markedly increased both the frequency and amplitude of miniature excitatory postsynaptic current in right hemisphere of insular cortex. Incubation of A347091 significantly decreased the frequency of spontaneous excitatory postsynaptic current and miniature excitatory postsynaptic current of insular cortex neurons of neonatal maternal deprivation rats. Incubation of P2X3Rs agonists α,β-mATP remarkably increased the frequency of spontaneous excitatory postsynaptic current and miniature excitatory postsynaptic current of the right hemisphere of insular cortex neurons of healthy control rats. Importantly, injection of A317491 significantly enhanced the colorectal distension threshold of neonatal maternal deprivation rats, while injection of α,β-mATP into right but not left insular cortex markedly decreased the colorectal distension threshold in healthy control rats.ConclusionsOverall, our data provide integrated pharmacological, biochemical, and functional evidence demonstrating that P2X3Rs are physically and functionally interconnected at the presynaptic level to control synaptic activities in the right insular cortex, thus contributing to visceral pain of neonatal maternal deprivation rats.

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“…For behavioral tests and molecular measurements, AAV-NC or AAV-P2X4R from Genechem Co. Ltd (Shanghai, China) was stereotaxically microinjected into the hippocampus of T2DM rats as described in our previous study [22]. Briefly, after the rat was anesthetized by intraperitoneal injection of 4% chloral hydrate, a microinjector was fixed unilaterally to the left side of the skull and aimed at the hippocampus (coordinates with respect to bregma: AP -4.8 mm, ML 3.2 mm, DV 3.5 mm, angle 0°) or at the right hippocampus.…”

Section: Microinjection Of Adeno-associated Virus (Aav)mentioning

confidence: 99%

“…ATP that supplies energy for cellular metabolism can be released into the extracellular space and play an important role via purinergic 2 receptors (P2Rs) in mediating neurotransmission as well as Ca 2? waves between astrocytic glial cells [21,22]. In addition, ATP released locally from damaged tissue induces microgliosis, and activated microglial cells migrate to the site of injury, proliferate, and phagocytose cells and cellular components [23].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Purinergic P2X4 Receptors in Hippocampus Rescues Memory Impairment in Rats with Type 2 Diabetes

Zhang

Sun

et al. 2020

Neurosci. Bull.

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Purinergic receptors have been reported to be involved in brain disorders. In this study, we explored their roles and mechanisms underlying the memory impairment in rats with type 2 diabetes mellitus (T2DM). T2DM rats exhibited a worse performance in the T-maze and Morris water maze (MWM) than controls. Microglia positive for P2X purinoceptor 4 (P2X4R) in the hippocampus were reduced and activated microglia were increased in T2DM rats. Long Amplicon PCR (LA-PCR) showed that DNA amplification of the p2x4r gene in the hippocampus was lower in T2DM rats. Minocycline significantly reduced the number of activated microglia and the mean distance traveled by T2DM rats in the MWM. Most importantly, P2X4R overexpression suppressed the activated microglia and rescued the memory impairment of T2DM rats. Overall, T2DM led to excessive activation of microglia in the hippocampus, partly through the DNA damagemediated downregulation of P2X4Rs, thus contributing to memory impairment.

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Neonatal Maternal Deprivation Enhances Presynaptic P2X7 Receptor Transmission in Insular Cortex in an Adult Rat Model of Visceral Hypersensitivity

Abstract: Data suggested that the enhanced activities of P2X7Rs in IC, likely through a presynaptic mechanism, contributed to visceral hypersensitivity of adult rats with NMD.

Cited by 20 publications

References 47 publications

Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach

Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach

Sensitization of P2X3 receptors in insular cortex contributes to visceral pain of adult rats with neonatal maternal deprivation

Overexpression of Purinergic P2X4 Receptors in Hippocampus Rescues Memory Impairment in Rats with Type 2 Diabetes

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