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Biomedical subjects

Min Zhuo

Publications and source records attributed to Min Zhuo.

At least 55 records · Page 3Linked to original sources
PubMed2004

Biphasic modulation of behavioral nociceptive responses by morphine in adult mice after amputation.

Amputation of a segment of the tail produced long-lasting changes in nociception and morphine-induced antinociception. Plastic changes in nociceptive transmission may occur at the spinal cord as well as supraspinal structures after tail amputation. Acute hyperalgesia is detected at the remaining part of the tail as well as hindpaw. Morphine induced facilitation of the hot-plate (HP) response at a low dose and a greater dose of morphine is required to produce complete inhibition of the HP response. Since these effects happen at five weeks after the surgery, tail amputation may serve as a mouse model for studying long-term plastic changes in central nervous system after amputation.

Amputation, Surgical↗
PubMed2004

Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord.

Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by extracellular protons. In periphery, they contribute to sensory transmission, including that of nociception and pain. Here we characterized ASIC-like currents in dorsal horn neurons of the rat spinal cord and their functional modulation in pathological conditions. Reverse transcriptase-nested PCR and Western blotting showed that three ASIC isoforms, ASIC1a, ASIC2a, and ASIC2b, are expressed at a high level in dorsal horn neurons. Electrophysiological and pharmacological properties of the proton-gated currents suggest that homomeric ASIC1a and/or heteromeric ASIC1a + 2b channels are responsible for the proton-induced currents in the majority of dorsal horn neurons. Acidification-induced action potentials in these neurons were compatible in a pH-dependent manner with the pH dependence of ASIC-like current. Furthermore, peripheral complete Freund's adjuvant-induced inflammation resulted in increased expression of both ASIC1a and ASIC2a in dorsal horn. These results support the idea that the ASICs of dorsal horn neurons participate in central sensory transmission/modulation under physiological conditions and may play important roles in inflammation-related persistent pain.

Acid Sensing Ion Channels↗
PubMed2004

Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein.

Amyloid-beta peptide (Abeta) is central to the pathogenesis of Alzheimer's disease, and the low-density lipoprotein receptor-related protein (LRP) has been shown to alter Abeta metabolism in vitro. Here, we show that overexpression of a functional LRP minireceptor in the brain of PDAPP mice results in age-dependent increase of soluble brain Abeta, with no changes in Abeta plaque burden. Importantly, soluble brain Abeta was found to be primarily in the form of monomers/dimers and to be highly correlated with deficits in spatial learning and memory. These results provide in vivo evidence that LRP may contribute to memory deficits typical of Alzheimer's disease by modulating the pool of small soluble forms of Abeta.

Amyloid beta-Peptides↗
PubMed2004

Modulation of presynaptic activity by phosphorylation in cultured rat spinal dorsal horn neurons.

UNLABELLED: Phosphorylation, in particular by protein kinase C (PKC), modulates spinal sensory transmission and nociceptive behaviors. Whereas PKC's postsynaptic actions are well established, its presynaptic effects in spinal sensory neurons are mostly inferred from postsynaptic recordings. Here we first show that the amphipathic styryl dye FM 1-43 can be used to image presynaptic activity in cultured spinal dorsal horn cultures and then test whether PKC modulates presynaptic activity in cultured spinal dorsal horn neurons. Pretreatment with the broad-spectrum kinase inhibitor staurosporine (2 micromol/L) inhibited dye release. Bisindolylmaleimide I, a PKC inhibitor, potentiated dye release at low doses (200 nmol/L and 1 micromol/L), while inhibiting it at a higher dose (5 micromol/L). Activating PKC with phorbol dibutyrate (0.5 micromol/L) induced an increase in exocytosis, which is partially blocked by bisindolylmaleimide I. These results indicate that styryl dyes can be used to observe presynaptic regulation of spinal dorsal horn neurons, and that PKC acts presynaptically to modulate spinal sensory transmission. PERSPECTIVE: With dye imaging technique, we demonstrate here that PKC presynaptically regulates sensory transmission in spinal dorsal horn neurons. In combination with conventional whole-cell patch-clamp recording technique, the present study provides a new methodology for studying spinal sensory transmission and modulation and facilitates our understanding of pain mechanism.

Animals↗
PubMed2004

Endogenous facilitation: from molecular mechanisms to persistent pain.

It is well documented that sensory transmission, including pain, is subject to endogenous inhibitory modulatory influences at dorsal horn of the spinal cord. Recent results, from behavioral to molecular studies, demonstrate that endogenous modulatory systems are bi-phasic, including inhibitory as well as new facilitatory systems. In this review, we propose the existence of endogenous facilitatory systems in the brain, and review evidence supporting the hypothesis. We believe that understanding molecular and cellular mechanisms of endogenous facilitatory systems hold the hope for better future treatment of patients with chronic pain.

Animals↗
PubMed2004

Central plasticity in pathological pain.

Neurons and synapses in the central nervous systems are very dynamic and plastic, and can undergo changes throughout life. Studies of molecular and cellular mechanisms of such changes not only provide important insight into how we learn and store new knowledge in our brains, but also reveal the mechanisms of pathological changes occurring following an injury. Here, we propose that while neuronal mechanisms underlying physiological functions such as learning and memory may share some common signalling molecules with abnormal or injury-related changes in the brain, distinct synaptic mechanisms are involved in pathological pain as compared with that of cognitive learning and memory. Using genetically altered mice and classic physiological approaches, we showed that N-methyl-D-aspartate (NMDA) receptor-dependent, calcium-calmodulin-activated adenylyl cyclases (AC1 and AC8) in the anterior cingulate cortex (ACC) play important roles in the induction and expression of persistent inflammatory and neuropathic pain. In contrast, acute pain was not significantly affected. Calcium-calmodulin-dependent protein kinase IV, which is widely expressed in central areas related to pain and memory, primarily contributes to injury-related fearful memory and emotional responses. Our studies suggest distinct signalling pathways are responsible for physiological responses to the injury, including behavioural, emotional and memory.

Adenylyl Cyclases↗
PubMed2003

Calmodulin regulates synaptic plasticity in the anterior cingulate cortex and behavioral responses: a microelectroporation study in adult rodents.

We developed a microelectroporation method for the transfer of genes into neurons in the cerebral cortex of adult rodents, both rats and mice. We selectively expressed either green-fluorescent protein (GFP) or a Ca2+-binding deficient calmodulin (CaM) mutant in the anterior cingulate cortex (ACC). In mice that expressed GFP, positive neuronal cell bodies were found specifically at the injection site in the ACC. Mice that expressed CaM12, a mutant CaM with two impaired Ca2+ binding sites in the N-terminal lobe, exhibited significant changes in vocalization, locomotion, and sensory functions. Long-term potentiation and long-term depression, two major forms of central plasticity, were completely abolished by expression of CaM12. Mice that expressed CaM34, a mutant CaM with two impaired Ca2+ binding sites in the C-terminal lobe, did not show any significant behavioral or electrophysiological alterations. These findings provide strong evidence that CaM is critical for bidirectional synaptic plasticity. This new method will be useful for investigating gene function in specific brain regions of freely moving animals. Furthermore, this approach also may facilitate gene therapy in adult human brains.

Animals↗
PubMed2003

NMDA receptors contribute to synaptic transmission in anterior cingulate cortex of adult mice.

Glutamatergic synapses are common excitatory chemical connections in mammalian central nervous system. At these synapses, most of baseline synaptic transmission is mediated by glutamate AMPA receptors. NMDA receptors that are sensitive to voltage-dependent magnesium blockade selectively contribute to activity-dependent synaptic plasticity. However, inhibition of NMDA receptors by systemic or local administration of NMDA receptor antagonists produced significant effects on different physiological functions that are not believed to depend on NMDA receptor related synaptic plasticity. Here we show that NMDA receptors contribute to synaptic responses in the anterior cingulate cortex (ACC), a region important for cognitive and other brain functions. The contribution of NMDA receptors became more prominent when synapses are stimulated at higher frequencies. Furthermore, at temperatures more close to physiological brain temperatures, more NMDA receptor mediated responses were recorded as compared to the room temperature. These data suggest a new function for NMDA receptors in the ACC as important postsynaptic receptors involved in synaptic transmission, in particular when cells are firing at high frequencies.

Animals↗
PubMed2003

Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein.

Modification of synaptic NMDA receptor (NMDAR) expression influences NMDAR-mediated synaptic function and associated persistent pain. NMDARs directly bind to a family of membrane-associated guanylate kinases (MAGUKs) that regulate surface and synaptic NMDAR trafficking in the CNS. We report here that postsynaptic density-93 protein (PSD-93), a postsynaptic neuronal MAGUK, is expressed abundantly in spinal dorsal horn and forebrain, where it colocalizes and interacts with NMDAR subunits NR2A and NR2B. Targeted disruption of the PSD-93 gene reduces not only surface NR2A and NR2B expression but also NMDAR-mediated excitatory postsynaptic currents and potentials, without affecting surface AMPA receptor expression or its synaptic function, in the regions mentioned above. Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain. PSD-93 appears to be important for NMDAR synaptic targeting and function and to be a potential biochemical target for the treatment of persistent pain.

Animals↗
PubMed2003

The high diversity of snoRNAs in plants: identification and comparative study of 120 snoRNA genes from Oryza sativa.

Using a powerful computer-assisted analysis strategy, a large-scale search of small nucleolar RNA (snoRNA) genes in the recently released draft sequence of the rice genome was carried out. This analysis identified 120 different box C/D snoRNA genes with a total of 346 gene variants, which were predicted to guide 135 2'-O-ribose methylation sites in rice rRNAs. Though not exhaustive, this analysis has revealed that rice has the highest number of known box C/D snoRNAs among eukaryotes. Interestingly, although many snoRNA genes are conserved between rice and Arabidopsis, almost half of the identified snoRNA genes are rice specific, which may highlight further the differences in rRNA methylation patterns between monocotyledons and dicotyledons. In addition to 76 singletons, 70 clusters involving 270 snoRNA genes were also found in rice. The large number of the novel snoRNA polycistrons found in the introns of rice protein-coding genes is in contrast to the one-snoRNA-per-intron organization of vertebrates and yeast, and of Arabidopsis in which only a few intronic snoRNA gene clusters were identified. Furthermore, due to a high degree of gene duplication, rice snoRNA genes are clearly redundant and exhibit great sequence variation among isoforms, allowing generation of new snoRNAs for selection. Thus, the large snoRNA gene family in plants can serve as an excellent model for a rapid and functional evolution.

Base Sequence↗
PubMed2003

Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain.

By integrating convergent protein engineering and rational inhibitor design, we have developed an in vivo conditional protein knockout andor manipulation technology. This method is based on the creation of a specific interaction interface between a modified protein domain and sensitized inhibitors. By introducing this system into genetically modified mice, we can readily manipulate the activity of a targeted protein, such as alpha-Ca(2+)calmodulin-dependent protein kinase II (alphaCAMKII), on the time scale of minutes in specific brain subregions of freely behaving mice. With this inducible and region-specific protein knockout technique, we analyzed the temporal stages of memory consolidation process and revealed the first postlearning week as the critical time window during which a precise level of CaMKII reactivation is essential for the consolidation of long-term memories in the brain.

Amino Acid Sequence↗
PubMed2003

Synaptic and molecular mechanisms of glutamatergic synapses in pain and memory.

Glutamate is a fast excitatory transmitter in mammalian brains. Glutamatergic synapses are found in central regions related to pain transmission, plasticity and modulation. Glutamate NMDA receptors in forebrain structures are well known to contribute to the formation and storage of information. Here we propose the hypothesis that forebrain NMDA receptors play an important role in persistent inflammatory pain by re-enforcing glutamate sensory transmission in the brain. Mice with enhanced function of forebrain NMDA receptors demonstrate selective enhancement of persistent pain and allodynia. Drugs targeting forebrain NMDA NR2B receptors may serve as a new class of medicine to control persistent pain in humans.

Animals↗
PubMed2002

Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases.

Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.

Adenylyl Cyclases↗
PubMed2002

Kainate receptor subunits underlying presynaptic regulation of transmitter release in the dorsal horn.

Presynaptic kainate (KA) receptors regulate synaptic transmission at both excitatory and inhibitory synapses in the spinal cord dorsal horn. Previous work has demonstrated pharmacological differences between the KA receptors expressed by rat dorsal horn neurons and those expressed by the primary afferent sensory neurons that innervate the dorsal horn. Here, neurons isolated from KA receptor subunit-deficient mice were used to evaluate the contribution of glutamate receptor subunit 5 (GluR5) and GluR6 to the presynaptic control of transmitter release and to KA receptor-mediated whole-cell currents in these two cell populations [corrected]. Deletion of GluR6 produced a significant reduction in KA receptor-mediated current density in dorsal horn neurons, whereas GluR5 deletion caused no change in current density but removed sensitivity to GluR5-selective antagonists. Presynaptic modulation of inhibitory transmission between dorsal horn neurons was preserved in cells from either GluR5- or GluR6-deficient mice. In DRG neurons, in contrast, GluR5 deletion abolished KA receptor function, whereas deletion of GluR6 had little effect on peak current density but increased the rate and extent of desensitization. These results highlight fundamental differences in KA receptor physiology between the two cell types and suggest possible strategies for the pharmacological modulation of nociception.

Action Potentials↗
PubMed2002

Glutamate receptors and persistent pain: targeting forebrain NR2B subunits.

Glutamate is the fast excitatory transmitter in mammalian brains. It binds to two major classes of glutamate receptors: ionotropic and metabotropic receptors. Ionotropic receptors contain three subtype receptors, including N-methyl-d-aspartate (NMDA) receptors. Activation of NMDA receptors is important for initiating long-lasting changes in synapses. In the forebrain structures that are known to contribute to the formation and storage of information, NMDA receptors have an important role in persistent inflammatory pain by reinforcing glutamate sensory transmission. Mice with enhanced forebrain NMDA receptor function demonstrate selective enhancement of persistent pain and allodynia. Drugs targeting NMDA NR2B subunits in the forebrain could serve as a new class of medicine for controlling persistent pain in humans.

Animals↗
PubMed2002

Activation of brainstem metabotropic glutamate receptors inhibits spinal nociception in adult rats.

In this study, we provide evidence that focal electrical stimulation applied to the rostroventral medulla (RVM) at a high frequency (100 Hz) produced inhibition of the spinal nociceptive tail-flick (TF) reflex in lightly anesthetized adult rats. Chemical activation of metabotropic glutamate (mGlu) receptors by local injection of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (tACPD), the mGlu receptor agonist, produced a dose-related inhibition of the TF reflex. Injection of the Group II mGlu receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCGIV) produced strong inhibition, while injection of the Group III mGlu receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) did not produce any effect. (RS)-alpha-Methyl-4-carboxyphenylglycine (MCPG), a selective mGlu receptor antagonist, but not naloxone reversed the inhibitory effects of DCGIV. Our results provide physiological evidence in vivo that activation of Group II mGlu receptors in the brainstem is antinociceptive and drugs targetting these receptors may help to control pain in humans.

Analgesics↗
PubMed2002

Calcium calmodulin-dependent protein kinase IV is required for fear memory.

The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV(-/-) mice--which are deficient in a component of the calcium calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation--fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.

Amygdala↗