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Biomedical subjects

M Zhuo

Publications and source records attributed to M Zhuo.

At least 19 recordsLinked to original sources
PubMed2005

Prolonged membrane potential depolarization in cingulate pyramidal cells after digit amputation in adult rats.

The anterior cingulate cortex (ACC) plays an important role in higher brain functions including learning, memory, and persistent pain. Long-term potentiation of excitatory synaptic transmission has been observed in the ACC after digit amputation, which might contribute to plastic changes associated with the phantom pain. Here we report a long-lasting membrane potential depolarization in ACC neurons of adult rats after digit amputation in vivo. Shortly after digit amputation of the hind paw, the membrane potential of intracellularly recorded ACC neurons quickly depolarized from approximately -70 mV to approximately -15 mV and then slowly repolarized. The duration of this amputation-induced depolarization was about 40 min. Intracellular staining revealed that these neurons were pyramidal neurons in the ACC. The depolarization is activity-dependent, since peripheral application of lidocaine significantly reduced it. Furthermore, the depolarization was significantly reduced by a NMDA receptor antagonist MK-801. Our results provide direct in vivo electrophysiological evidence that ACC pyramidal cells undergo rapid and prolonged depolarization after digit amputation, and the amputation-induced depolarization in ACC neurons might be associated with the synaptic mechanisms for phantom pain.

Journal Article↗
PubMed2002

Oxytocin mediates stress-induced analgesia in adult mice.

As a neurohormone and as a neurotransmitter, oxytocin has been implicated in the stress response. Descending oxytocin-containing fibres project to the dorsal horn of the spinal cord, an area important for processing nociceptive inputs. Here we tested the hypothesis that oxytocin plays a role in stress-induced analgesia and modulates spinal sensory transmission. Mice lacking oxytocin exhibited significantly reduced stress-induced antinociception following both cold-swim (10 degrees C, 3 min) and restraint stress (30 min). In contrast, the mice exhibited normal behavioural responses to thermal and mechanical noxious stimuli and morphine-induced antinociception. In wild-type mice, intrathecal injection of the oxytocin antagonist dOVT (200 microM in 5 microl) significantly attenuated antinociception induced by cold-swim. Immunocytochemical staining revealed that, in the mouse, oxytocin-containing neurones in the paraventricular nucleus of the hypothalamus are activated by stress. Furthermore, oxytocin-containing fibres were present in the dorsal horn of the spinal cord. To test whether descending oxytocin-containing fibres could alter nociceptive transmission, we performed intracellular recordings of dorsal horn neurones in spinal slices from adult mice. Bath application of oxytocin (1 and 10 microM) inhibited excitatory postsynaptic potentials (EPSPs) evoked by dorsal root stimulation. This effect was reversed by the oxytocin antagonist dOVT (1 microM). Whole-cell recordings of dorsal horn neurones in postnatal rat slices revealed that the effect of oxytocin could be blocked by the addition of GTP-gamma-S to the recording pipette, suggesting activation of postsynaptic oxytocin receptors. We conclude that oxytocin is important for both cold-swim and restraint stress-induced antinociception, acting by inhibiting glutamatergic spinal sensory transmission.

Analgesia↗
PubMed2002

Modulation of noxious and non-noxious spinal mechanical transmission from the rostral medial medulla in the rat.

Modulatory influences on spinal mechanical transmission from the rostral medial medulla (RMM) were studied. Noxious stimulation, produced by von Frey-like monofilaments, and non-noxious stimulation, produced by a soft brush, was applied to the glabrous skin of the hind foot. At 28 sites in RMM, electrical stimulation facilitated responses to noxious mechanical stimulation at low intensities (5-25 microA) and inhibited responses of the same neurons at greater intensities (50-100 microA) of stimulation. At 24 and 9 other sites in RMM, stimulation at all intensities only inhibited or only facilitated, respectively, responses to noxious mechanical stimulation of the hind foot. Stimulus-response functions to mechanical stimulation were shifted leftward by low intensities and decreased by high intensities of stimulation. Inhibitory influences were found to descend in the dorsolateral funiculi; facilitatory effects were contained in the ventral spinal cord. Descending modulation of non-noxious brush stimulation revealed biphasic facilitatory-inhibitory effects (9 sites in RMM), only inhibitory effects (14 sites) and only facilitatory effects (8 sites). The effects of electrical stimulation were replicated by intra-RMM administration of glutamate; a low concentration (0.25 nmol) facilitated and a greater concentration (2.5 nmol) inhibited spinal mechanical transmission, providing evidence that cells in RMM are sufficient to engage descending influences. Descending modulatory effects were specific for the site of stimulation, not for the spinal neuron, because modulation of the same neuron was different from different sites in RMM. These results show that spinal mechanical transmission, both noxious and non-noxious, is subject to descending influences, including facilitatory influences that may contribute to exaggerated responses to peripheral stimuli in some chronic pain states.

Animals↗
PubMed2002

Biphasic modulation of spinal visceral nociceptive transmission from the rostroventral medial medulla in the rat.

Descending inhibitory and facilitatory influences from the rostroventral medulla (RVM) on responses of lumbosacral spinal neurons to noxious colorectal distension (CRD, 80 mmHg, 20 s) were studied. At 25 sites in the RVM, electrical stimulation produced biphasic effects, facilitating responses of spinal neurons to CRD at lesser intensities of stimulation (5-25 microA) and inhibiting responses of the same neurons at greater intensities of stimulation (50-100 microA). At 38 other sites in the RVM, electrical stimulation produced only intensity-dependent inhibition of neuron responses to CRD. At another 13 sites in the RVM, electrical stimulation (5-100 microA) produced only facilitatory effects on responses to CRD. Descending modulatory effects were selective for distension-evoked activity; spontaneous activities of the same spinal neurons were not significantly affected by electrical stimulation that either facilitated or inhibited neuron responses to CRD. Neuron responses to graded CRD (20-100 mmHg) were positively accelerating functions that were shifted leftward or rightward, respectively, by lesser, facilitatory intensities or greater, inhibitory intensities of RVM stimulation. L-glutamate microinjection into the RVM replicated the effects of electrical stimulation, producing similar biphasic modulatory effects as produced by electrical stimulation. Microinjection of glutamate into the RVM at a low dose (5 nmoles) facilitated responses of spinal neurons to CRD and inhibited responses of the same neurons at a greater dose (50 nmoles). In some experiments, microinjection of lidocaine (0.5 microl of 4% solution) or the neurotoxin ibotenic acid (0.5 microl, 10 microg) into the RVM produced reversible or long-lasting, respectively, decreases in spontaneous activity and responses of spinal neurons to CRD. These results reveal that spinal visceral nociceptive transmission is subject to a tonic descending excitatory influence from the RVM and that descending modulatory effects from the RVM on visceral nociceptive transmission are qualitatively similar to modulation of cutaneous nociceptive transmission.

Animals↗
PubMed2001

Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism.

In the spinal cord dorsal horn, excitatory sensory fibers terminate adjacent to interneuron terminals. Here, we show that kainate (KA) receptor activation triggered action potential-independent release of GABA and glycine from dorsal horn interneurons. This release was transient, because KA receptors desensitized, and it required Na+ entry and Ca2+ channel activation. KA modulated evoked inhibitory transmission in a dose-dependent, biphasic manner, with suppression being more prominent. In recordings from isolated neuron pairs, this suppression required GABA(B) receptor activation, suggesting that KA-triggered GABA release activated presynaptic GABA(B) autoreceptors. Finally, glutamate released from sensory fibers caused a KA and GABA(B) receptor-dependent suppression of inhibitory transmission in spinal slices. Thus, we show how presynaptic KA receptors are linked to changes in GABA/glycine release and highlight a novel role for these receptors in regulating sensory transmission.

Action Potentials↗
PubMed2001

Substance P and neurokinin A mediate sensory synaptic transmission in young rat dorsal horn neurons.

Spinal nociceptive transmission is mediated by glutamate and neuropeptides such as substance P (SP) and neurokinin A (NKA). The neuropeptide-mediated excitatory postsynaptic potentials (EPSPs) had a slow onset and long duration. Here, we demonstrate SP- and NKA-mediated excitatory postsynaptic currents (EPSCs) in dorsal horn neurons of young rats using whole-cell patch-clamp recording techniques. After complete blockade of glutamate receptor-mediated currents, we observed a small residual EPSC. The residual EPSCs exhibited temporal summation in response to a train of stimulation (six pulses delivered at 10-50 Hz). High intensity stimulation (the same or greater than the stimulation threshold for nociceptive fibers in vivo) was required for evoking these summated EPSCs. Summated EPSCs were attenuated or abolished by capsaicin pretreatment, which depletes SP and NKA from presynaptic terminals; SP and NKA pretreatment; NK(1) or NK(2) receptor antagonists; and inhibition of postsynaptic G proteins. EPSCs were neither blocked by a metabotropic glutamate receptor antagonist nor a gamma-aminobutyric acid(B) receptor antagonist. The summated EPSCs were also sensitive to voltage-gated calcium channel antagonists or mu-opioid receptor activation by DAMGO. The present study provides electrophysiological evidence that suggests the possible contribution of SP and NKA to sensory synaptic transmission between primary afferent fibers and dorsal horn neurons.

2-Amino-5-phosphonovalerate↗
PubMed2001

No pain, no gains.

No pain, no gains. Pain and memory are two critical functions of animals and humans. Through painful experience humans and animals learn what is potentially harmful and then store this information in the brain in order to avoid future injury. It is the essential skill for animals and humans to survive through their lifespan. However, it is unclear if both processes may share common signal molecules or proteins in the brain. It is known that the NMDA receptor, a receptor for glutamate, in the higher structures of the brain is important for memory formation and storage. NMDA receptors in the spinal cord contribute to central sensitization of sensory information such as pain after injuries.

Animals↗
PubMed2001

Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat.

The anterior cingulate cortex (ACC) is important for processing different types of information, including sensory inputs. In the present study on anaesthetised rats, we recorded in vivo sensory responses of the ACC to peripheral electrical shocks. Peripheral electrical stimulation at high intensities sufficient to activate nociceptive sensory fibres elicited EPSPs within the ACC. Digit amputation caused long-lasting potentiation of ACC responses to peripheral electrical stimulation. Evoked field EPSPs remained enhanced for at least 120 min after the amputation. Because electrical shocks were delivered to the normal hindpaw, it is likely that plastic changes occur centrally in the spinal cord or the supraspinal structures following amputation. We also recorded field EPSPs of the ACC in response to focal cortical stimulation within the ACC. Like the sensory responses, field EPSPs produced by focal cortical stimulation within the ACC were potentiated after digit amputation, suggesting that long-lasting changes occurred locally within the ACC. Local blockade of peripheral activity by QX-314 at the amputated hindpaw 120 min after amputation did not significantly affect sensory responses induced within the ACC. Thus, peripheral ongoing inputs do not play an important role in maintaining potentiation within the ACC. Two pulses of hindpaw stimulation caused paired-pulse depression in the ACC. Local stimulation within the ACC also caused depression of sensory responses to hindpaw stimulation, suggesting that the population of synapses activated by local stimulation may overlap with that activated by peripheral hindpaw stimulation. Our results suggest that rapid enhancement of sensory responses can be observed in the ACC after amputation and that enhanced neuronal responses to subsequent somatosensory stimuli may contribute to phantom-limb pain.

Amputation, Surgical↗
PubMed2001

Presynaptic kainate receptors regulate spinal sensory transmission.

Small diameter dorsal root ganglion (DRG) neurons, which include cells that transmit nociceptive information into the spinal cord, are known to express functional kainate receptors. It is well established that exposure to kainate will depolarize C-fiber afferents arising from these cells. Although the role of kainate receptors on sensory afferents is unknown, it has been hypothesized that presynaptic kainate receptors may regulate glutamate release in the spinal cord. Here we show that kainate, applied at low micromolar concentrations in the presence of the AMPA-selective antagonist (RS)-4-(4-aminophenyl)-1, 2-dihydro-1-methyl-2-propyl-carbamoyl-6,7-methylenedioxyphthalazine++ +, suppressed spontaneous NMDA receptor-mediated EPSCs in cultures of spinal dorsal horn neurons. In addition, kainate suppressed EPSCs in dorsal horn neurons evoked by stimulation of synaptically coupled DRG cells in DRG-dorsal horn neuron cocultures. Interestingly, although the glutamate receptor subunit 5-selective kainate receptor agonist (RS)-2-alpha-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) (2 micrometer) was able to suppress DRG-dorsal horn synaptic transmission to a similar extent as kainate (10 micrometer), it had no effect on excitatory transmission between dorsal horn neurons. Agonist applications revealed a striking difference between kainate receptors expressed by DRG and dorsal horn neurons. Whereas DRG cell kainate receptors were sensitive to both kainate and ATPA, most dorsal horn neurons responded only to kainate. Finally, in recordings from dorsal horn neurons in spinal slices, kainate and ATPA were able to suppress NMDA and AMPA receptor-mediated EPSCs evoked by dorsal root fiber stimulation. Together, these data suggest that kainate receptor agonists, acting at a presynaptic locus, can reduce glutamate release from primary afferent sensory synapses.

Animals↗
PubMed2001

Cholinergic, noradrenergic, and serotonergic inhibition of fast synaptic transmission in spinal lumbar dorsal horn of rat.

It is known that spinal nociceptive sensory transmission receives descending inhibitory and facilitatory modulation from supraspinal structures. Glutamate is the major fast excitatory transmitter between primary afferent fibers and spinal dorsal horn neurons. In whole-cell patch clamp recordings from dorsal horn neurons in spinal slices, we investigated synaptic mechanisms for inhibitory modulation at the lumbar level of the spinal cord. Application of the cholinergic receptor agonist carbachol produced a dose-dependent inhibition of glutamate-mediated excitatory postsynaptic currents (EPSCs) (IC(50) 13 microM). Postsynaptic injection of two different types of G-protein inhibitors, guanosine 5'-O-2-thiophosphate or guanosine 5'-O-3-thiotriphosphate, blocked the inhibition produced by carbachol. Clonidine, a selective alpha-adrenergic receptor agonist, also produced a dose-dependent inhibition of EPSCs (IC(50) 7 microM) that was reduced by postsynaptic inhibition of G-proteins. The inhibitory effect of serotonin was likewise mediated by postsynaptic G-proteins. Our results suggest that activation of postsynaptic neurotransmitter receptors plays a critical role in inhibition of glutamate mediated sensory responses by acetylcholine, norepinephrine, and serotonin. Our results support the hypothesis that descending sensory modulation may be mediated by multiple neurotransmitter receptors in the spinal cord.

Acetylcholine↗
PubMed2001

Genetic enhancement of inflammatory pain by forebrain NR2B overexpression.

N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions. We studied the effect of forebrain-targeted overexpression of the NMDA receptor subunit NR2B on the response of mice to tissue injury and inflammation. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord. Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective agents, may be useful analgesics for persistent pain.

Animals↗
PubMed2001

A-6G variant of the angiotensinogen gene and essential hypertension in Han, Tibetan, and Yi populations.

To investigate the relationship between the A-6G variant in the promoter of the angiotensinogen gene and essential hypertension in Han, Tibetan, and Yi populations. All patients with essential hypertension were selected by WHO criteria. And the polymorphism of the A-6G variant was determined by PCR/RFLP. The data were analyzed by t test and chi2 test. There was no significant difference in the genotype or allele frequencies between normotensives and hypertensives in the Han, Tibetan, and Yi populations, respectively. However, when the subjects were divided into male and female subgroups, the genotype distributions among hypertensives and normotensives of the Tibetan female group were as follows: AA, 37% vs. 48%; AG, 52% vs. 48%; GG, 11% vs. 4%, respectively and the frequency of the G allele was significantly higher in hypertensives than in normotensives in the Tibetan female group (0.37 vs. 0.28, chi2=4.25, p<0.05). In addition, we observed that there was a significant difference between the Han and Tibetan normotensive groups in the distributions of the allele and genotype frequencies of the A-6G variant. The frequency of the G allele was 0.29 and 0.17 in the Tibetan normotensive and Han groups, respectively (p<0.001). The G allele of the A-6G variant was associated with hypertension in the Tibetan females, but not in the Yi or Han females. And we confirmed that there was a significant difference in the prevalence of the allele frequencies of the A-6G variant between the Han and Tibetan normotensive groups.

Adult↗
PubMed2000

Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice.

The Ca(2+)/calmodulin-dependent protein kinase type IV/Gr (CaMKIV/Gr) is a key effector of neuronal Ca(2+) signaling; its function was analyzed by targeted gene disruption in mice. CaMKIV/Gr-deficient mice exhibited impaired neuronal cAMP-responsive element binding protein (CREB) phosphorylation and Ca(2+)/CREB-dependent gene expression. They were also deficient in two forms of synaptic plasticity: long-term potentiation (LTP) in hippocampal CA1 neurons and a late phase of long-term depression in cerebellar Purkinje neurons. However, despite impaired LTP and CREB activation, CaMKIV/Gr-deficient mice exhibited no obvious deficits in spatial learning and memory. These results support an important role for CaMKIV/Gr in Ca(2+)-regulated neuronal gene transcription and synaptic plasticity and suggest that the contribution of other signaling pathways may spare spatial memory of CaMKIV/Gr-deficient mice.

Animals↗
PubMed2000

Spinophilin regulates the formation and function of dendritic spines.

Spinophilin, a protein that interacts with actin and protein phosphatase-1, is highly enriched in dendritic spines. Here, through the use of spinophilin knockout mice, we provide evidence that spinophilin modulates both glutamatergic synaptic transmission and dendritic morphology. The ability of protein phosphatase-1 to regulate the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors was reduced in spinophilin knockout mice. Consistent with altered glutamatergic transmission, spinophilin-deficient mice showed reduced long-term depression and exhibited resistance to kainate-induced seizures and neuronal apoptosis. In addition, deletion of the spinophilin gene caused a marked increase in spine density during development in vivo as well as altered filopodial formation in cultured neurons. In conclusion, spinophilin appears to be required for the regulation of the properties of dendritic spines.

Animals↗
PubMed2000

Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice.

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. To define the molecular pathways involved in the response to stress further, we generated mice deficient (KO) in the calcium-stimulated adenylyl cyclase type VIII (AC8) by homologous recombination in embryonic stem cells. AC8 KO mice demonstrate a compromise in calcium-stimulated AC activity in the hippocampus, hypothalamus, thalamus, and brainstem. Hippocampal slices derived from AC8 KO mice fail to demonstrate CA1-region long-term depression after low-frequency stimulation, and AC8 KO mice also fail to activate CRE-binding protein in the CA1 region after restraint stress. To define the behavioral consequences of AC8 deficiency, we evaluated AC8 KO mice in the elevated plus-maze and open field. Although naive AC8 KO mice exhibit indices of anxiety comparable with that of wild-type mice, AC8 KO mice do not show normal increases in behavioral markers of anxiety when subjected to repeated stress such as repetitive testing in the plus-maze or restraint preceding plus-maze testing. These results demonstrate a novel role for AC8 in the modulation of anxiety.

Adenylyl Cyclases↗
PubMed2000

Role of EGR1 in hippocampal synaptic enhancement induced by tetanic stimulation and amputation.

Hippocampal neurons fire spikes when an animal is at a particular location or performs certain behaviors in a particular place, providing a cellular basis for hippocampal involvement in spatial learning and memory. In a natural environment, spatial memory is often associated with potentially dangerous sensory experiences such as noxious or painful stimuli. The central sites for such pain-associated memory or plasticity have not been identified. Here we present evidence that excitatory glutamatergic synapses within the CA1 region of the hippocampus may play a role in storing pain-related information. Peripheral noxious stimulation induced excitatory postsynaptic potentials (EPSPs) in CA1 pyramidal cells in anesthetized animals. Tissue/nerve injury caused a rapid increase in the level of the immediate-early gene product Egr1 (also called NGFI-A, Krox24, or zif/268) in hippocampal CA1 neurons. In parallel, synaptic potentiation induced by a single tetanic stimulation (100 Hz for 1 s) was enhanced after the injury. This enhancement of synaptic potentiation was absent in mice lacking Egr1. Our data suggest that Egr1 may act as an important regulator of pain-related synaptic plasticity within the hippocampus.

Amputation, Surgical↗
PubMed2000

Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation.

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, alpha(2)-macroglobulin, and the beta-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.

Animals↗