Histone Methyltransferase G9a in Primary Sensory Neurons Promotes Inflammatory Pain and Transcription of and via Bivalent Histone Modifications.

Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels are crucial for detecting and transmitting nociceptive stimuli. Inflammatory pain is associated with sustained increases in TRPA1 and TRPV1 expression in primary sensory neurons. However, the epigenetic mechanisms driving this upregulation remain unknown.

mGluR5 from Primary Sensory Neurons Promotes Opioid-Induced Hyperalgesia and Tolerance by Interacting with and Potentiating Synaptic NMDA Receptors.

Aberrant activation of presynaptic NMDARs in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms responsible for opioid-induced NMDAR hyperactivity remain poorly identified. Here, we show that repeated treatment with morphine or fentanyl reduced monomeric mGluR5 protein levels in the dorsal root ganglion (DRG) but increased levels of mGluR5 monomers and homodimers in the spinal cord in mice and rats of both sexes.

NMDA Receptors at Primary Afferent-Excitatory Neuron Synapses Differentially Sustain Chemotherapy- and Nerve Trauma-Induced Chronic Pain.

The spinal dorsal horn contains vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons and vesicular GABA transporter (VGAT)-expressing inhibitory neurons, which normally have different roles in nociceptive transmission. Spinal glutamate NMDAR hyperactivity is a crucial mechanism of chronic neuropathic pain. However, it is unclear how NMDARs regulate primary afferent input to spinal excitatory and inhibitory neurons in neuropathic pain.

Brief Opioid Exposure Paradoxically Augments Primary Afferent Input to Spinal Excitatory Neurons via α2δ-1-Dependent Presynaptic NMDA Receptors.

Treatment with opioids not only inhibits nociceptive transmission but also elicits a rebound and persistent increase in primary afferent input to the spinal cord. Opioid-elicited long-term potentiation (LTP) from TRPV1-expressing primary afferents plays a major role in opioid-induced hyperalgesia and analgesic tolerance. Here, we determined whether opioid-elicited LTP involves vesicular glutamate transporter-2 (VGluT2) or vesicular GABA transporter (VGAT) neurons in the spinal dorsal horn of male and female mice and identified underlying signaling mechanisms.

HDAC2 in Primary Sensory Neurons Constitutively Restrains Chronic Pain by Repressing α2δ-1 Expression and Associated NMDA Receptor Activity.

α2δ-1 (encoded by the gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain.

α2δ-1 protein drives opioid-induced conditioned reward and synaptic NMDA receptor hyperactivity in the nucleus accumbens.

Glutamate NMDA receptors (NMDARs) in the nucleus accumbens (NAc) are critically involved in drug dependence and reward. α2δ-1 is a newly discovered NMDAR-interacting protein that promotes synaptic trafficking of NMDARs independently of its conventional role as a calcium channel subunit. However, it remains unclear how repeated opioid exposure affects synaptic NMDAR activity and α2δ-1-NMDAR interaction in the NAc.

δ-Opioid receptors in primary sensory neurons tonically restrain nociceptive input in chronic pain but do not enhance morphine analgesic tolerance.

δ-Opioid receptors (DORs, encoded by the Oprd1 gene) are expressed throughout the peripheral and central nervous system, and DOR stimulation reduces nociception. Previous studies suggest that DORs promote the development of analgesic tolerance of μ-opioid receptor (MOR) agonists. It is uncertain whether DORs expressed in primary sensory neurons are involved in regulating chronic pain and MOR agonist-induced tolerance.

Theta-Burst Stimulation of Primary Afferents Drives Long-Term Potentiation in the Spinal Cord and Persistent Pain via α2δ-1-Bound NMDA Receptors.

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions.

α2δ-1 Upregulation in Primary Sensory Neurons Promotes NMDA Receptor-Mediated Glutamatergic Input in Resiniferatoxin-Induced Neuropathy.

Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with α2δ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2δ-1 and GluN1 in the spinal cord synaptosomes.

The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons.

The metabotropic glutamate (mGlu) receptor 5 is a G protein-coupled receptor and is densely expressed in the mammalian brain. Like other glutamate receptors, mGlu5 receptors are tightly regulated by posttranslational modifications such as phosphorylation, although underlying mechanisms are incompletely investigated. In this study, we investigated the role of a prime kinase, extracellular signal-regulated kinase 1 (ERK1), in the phosphorylation and regulation of mGlu5 receptors in vitro and in striatal neurons.

Amphetamine activates non-receptor tyrosine kinase Fyn and stimulates ERK phosphorylation in the rat striatum in vivo.

The psychostimulant amphetamine (AMPH) has an impact on a variety of cellular activities in striatal neurons, although underlying signaling mechanisms are incompletely understood. The Src family kinase (SFK) is among key signaling molecules enriched in striatal neurons and is involved in the regulation of a set of discrete downstream targets. Given the likelihood that AMPH may regulate SFKs, we investigated and characterized the effect of AMPH on SFK phosphorylation and enzymatic activity in rat striatal neurons in vivo.

Inhibition of basal and amphetamine-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in the rat forebrain by muscarinic acetylcholine M4 receptors.

The mitogen-activated protein kinase (MAPK), especially its extracellular signal-regulated kinase (ERK) subfamily, is a group of kinases enriched in the mammalian brain. While ERK is central to cell signaling and neural activities, the regulation of ERK by transmitters is poorly understood. In this study, the role of acetylcholine in the regulation of ERK was investigated in adult rat striatum in vivo.

Regulation of Phosphorylation of AMPA Glutamate Receptors by Muscarinic M4 Receptors in the Striatum In vivo.

The acetylcholine muscarinic 4 (M4) receptor is a principal muscarinic receptor subtype present in the striatum. Notably, G-coupled M4 receptors and G/G-coupled dopamine D1 receptors are coexpressed in striatonigral projection neurons and are thought to interact with each other to regulate neuronal excitability, although underlying molecular mechanisms are poorly understood. In this study, we investigated the role of M4 receptors in the regulation of phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the rat normal and dopamine-stimulated striatum in vivo.

Pharmacological modulation of AMPA receptor phosphorylation by dopamine and muscarinic receptor agents in the rat medial prefrontal cortex.

Two key transmitters in the medial prefrontal cortex (mPFC), dopamine and acetylcholine, are believed to interact with each other to modulate local glutamatergic transmission, although molecular mechanisms underlying their crosstalk are poorly understood. Here we investigated effects of pharmacological manipulations of dopamine and muscarinic receptors on phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat mPFC in vivo. We found that an agonist selective for G-coupled dopamine D receptors, SKF81297, increased AMPA receptor GluA1 subunit phosphorylation at a protein kinase A-sensitive site (S845), while SKF81297 had no effect on GluA1 phosphorylation at S831.

An Essential Role of Fyn in the Modulation of Metabotropic Glutamate Receptor 1 in Neurons.

Fyn is a member of the Src family of nonreceptor tyrosine kinases and is broadly expressed in the CNS. As a synapse-enriched kinase, Fyn interacts with and phosphorylates local substrates to regulate synaptic transmission and plasticity, although our knowledge of specific targets of Fyn at synaptic sites remains incomplete and the accurate role of Fyn in regulating synaptic proteins is poorly understood. In this study, we initiated an effort to explore the interaction of Fyn with a metabotropic glutamate receptor (mGluR).

Integrated regulation of AMPA glutamate receptor phosphorylation in the striatum by dopamine and acetylcholine.

Dopamine (DA) and acetylcholine (ACh) signals converge onto protein kinase A (PKA) in medium spiny neurons of the striatum to control cellular and synaptic activities of these neurons, although underlying molecular mechanisms are less clear. Here we measured phosphorylation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) at a PKA site (S845) as an indicator of AMPAR responses in adult rat brains in vivo to explore how DA and ACh interact to modulate AMPARs. We found that subtype-selective activation of DA D1 receptors (D1Rs), D2 receptors (D2Rs), or muscarinic M4 receptors (M4Rs) induced specific patterns of GluA1 S845 responses in the striatum.

Amphetamine elevates phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the rat forebrain via activating dopamine D1 and D2 receptors.

Psychostimulants have an impact on protein synthesis, although underlying molecular mechanisms are unclear. Eukaryotic initiation factor 2α-subunit (eIF2α) is a key player in initiation of protein translation and is regulated by phosphorylation. While this factor is sensitive to changing synaptic input and is critical for synaptic plasticity, its sensitivity to stimulants is poorly understood.

Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII.

Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA receptors in adult rat striatal neurons.

Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors.

Dopamine and acetylcholine are two principal transmitters in the striatum and are usually balanced to modulate local neural activity and to maintain striatal homeostasis. This study investigates the role of dopamine and muscarinic acetylcholine receptors in the regulation of a central signaling protein, i.e.

Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine.

Increasing evidence supports the critical role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in psychostimulant action. These receptors are regulated via a phosphorylation-dependent mechanism in their trafficking, distribution, and function. The hippocampus is a brain structure important for learning and memory and is emerging as a critical site for processing psychostimulant effects.

Lipocalin 2 is a regulator of macrophage polarization and NF-κB/STAT3 pathway activation.

Lipocalin 2 (Lcn2) has been previously characterized as an adipokine/cytokine and implicated in obesity and inflammation. Herein, we investigated the role and potential mechanism of Lcn2 in the regulation of macrophage polarization in obesity-associated inflammation. We observed that Lcn2-/- mice displayed an up-regulation of expression of M1 macrophage marker Cd11c but a down-regulation of M2 marker arginase 1 in adipose tissue and liver of mice upon a high-fat diet feeding.

Phosphorylation and regulation of glutamate receptors by CaMKII.

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is the most abundant kinase within excitatory synapses in the mammalian brain. It interacts with and phosphorylates a large number of synaptic proteins, including major ionotropic glutamate receptors (iGluRs) and group I metabotropic glutamate receptors (mGluRs), to constitutively and/or activity-dependently regulate trafficking, subsynaptic localization, and function of the receptors. Among iGluRs, the N-methyl-D-aspartate receptor (NMDAR) is a direct target of CaMKII.

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission.

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated.

Increased miR-449a expression in colorectal carcinoma tissues is inversely correlated with serum carcinoembryonic antigen.

Previously, microRNA-449a (miR-449a) has been shown to be involved in various types of cancer. However, its role in colorectal carcinoma remains unknown. The present study found that miR-449a expression was significantly increased in cultured colorectal carcinoma cells and cancer tissues obtained from 24 patients diagnosed with colorectal carcinoma, compared with the normal colorectal cells and the adjacent non-tumor tissues.