Cingulate NMDA NR2B receptors contribute to morphine-induced analgesic tolerance.

Morphine is widely used to treat chronic pain, however its utility is hindered by the development of tolerance to its analgesic effects. While N-methyl-D-aspartate (NMDA) receptors are known to play roles in morphine tolerance and dependence, less is known about the roles of individual NMDA receptor subtypes. In this study, Ro 256981, an antagonist of the NMDA receptor subunit NR2B, was used to reduce the expression of analgesic tolerance to morphine.

Alteration of cingulate long-term plasticity and behavioral sensitization to inflammation by environmental enrichment.

Exposure to an enriched environment (EE) has been shown to induce cortical plasticity. Considerable amount of research is focused on the effects of EE in the hippocampus; however, effects of EE on other brain regions and the mechanisms involved are not well known. To investigate this, we induced cortical plasticity by placing mice in an EE for one month and measured the effects of EE in the anterior cingulate cortex (ACC).

Kainate receptors and pain: from dorsal root ganglion to the anterior cingulate cortex.

Ionotropic glutamate receptors contain three subtypes: NMDA, AMPA and kainate receptors. The former two receptor subtypes have well defined roles in nociception, while the role of kainate receptors in pain is not as well characterized. Kainate receptors are expressed in nociceptive pathways, including the dorsal root ganglion, spinal cord, thalamus and cortex.

Increased anxiety-like behavior and enhanced synaptic efficacy in the amygdala of GluR5 knockout mice.

GABAergic transmission in the amygdala modulates the expression of anxiety. Understanding the interplay between GABAergic transmission and excitatory circuits in the amygdala is, therefore, critical for understanding the neurobiological basis of anxiety. Here, we used a multi-disciplinary approach to demonstrate that GluR5-containing kainate receptors regulate local inhibitory circuits, modulate the excitatory transmission from the basolateral amygdala to the central amygdala, and control behavioral anxiety.

Hot receptors in the brain.

Two major approaches have been employed for the development of novel drugs to treat chronic pain. The most traditional approach identifies molecules involved in pain as potential therapeutic targets and has focused mainly on the periphery and spinal cord. A more recent approach identifies molecules that are involved in long-term plasticity.

Long-term memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alpha-deficient mice.

Signaling by the Ca(2+)/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase alpha (CaMKKalpha) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKalpha mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing.

Enhanced presynaptic neurotransmitter release in the anterior cingulate cortex of mice with chronic pain.

The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in learning and memory. Recent studies show that painful stimuli activate the prefrontal cortex and that brain chemistry is altered in this area in patients with chronic pain. Components of the CNS that are involved in pain transmission and modulation, from the spinal cord to the ACC, are very plastic and undergo rapid and long-term changes after injury.

CREB activity maintains the survival of cingulate cortical pyramidal neurons in the adult mouse brain.

Cyclic AMP-responsive element binding protein (CREB) activity is known to contribute to important neuronal functions, such as synaptic plasticity, learning and memory. Using a microelectroporation technique to overexpress dominant negative mutant CREB (mCREB) in the adult mouse brain, we found that overexpression of mCREB in the forebrain cortex induced neuronal degeneration. Our findings suggest that constitutively active CREB phosphorylation is important for the survival of mammalian cells in the brain.

Evidence for a role of CaMKIV in the development of opioid analgesic tolerance.

cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV). Here, we show that CaMKIV-knockout (KO) mice developed less analgesic tolerance after chronic morphine administration with no alteration in physical dependence or acute morphine-induced analgesia. The increase in phosphorylated CREB expression observed in wild-type mice after chronic morphine was absent in CaMKIV-KO mice, while there was no difference in the expression or phosphorylation of the micro-opioid receptor between groups.

Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation.

Transgenic overexpression of NMDA NR2B receptors in forebrain regions increased behavioral responses to persistent inflammatory pain. However, it is not known whether inflammation leads to the upregulation of NR2B receptors in these regions. Here, we show that peripheral inflammation increased the expression of NMDA NR2B receptors and NR2B receptor-mediated synaptic currents in the anterior cingulate cortex (ACC).

Feed-forward inhibition: a novel cellular mechanism for the analgesic effect of substance P.

Substance P (SP) is a neuropeptide well known for its contribution to pain transmission in the spinal cord, however, less is known about the possible modulatory effects of SP. A new study by Gu and colleagues, published in Molecular Pain (2005, 1:20), describes its potential role in feed-forward inhibition in lamina V of the dorsal horn of the spinal cord. This inhibition seems to function through a direct excitation of GABAergic interneurons by substance P released from primary afferent fibers and has a distinct temporal phase of action from the well-described glutamate-dependent feed-forward inhibition.

Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory.

Cortical plasticity is thought to be important for the establishment, consolidation, and retrieval of permanent memory. Hippocampal long-term potentiation (LTP), a cellular mechanism of learning and memory, requires the activation of glutamate N-methyl-D-aspartate (NMDA) receptors. In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus.

Genetic alteration of anxiety and stress-like behavior in mice lacking CaMKIV.

Calcium-calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates the major transcription factor cyclic AMP-response element binding protein (CREB), which plays a role in emotional behavior. Here, CaMKIV knockout mice (CaMKIV(-/-)) were tested in a battery of stress and anxiety-related behavioral tests, to determine if CaMKIV plays a role in emotional behavior. CaMKIV(-/-) exhibited a decrease in anxiety-like behavior in both the elevated plus maze and dark-light emergence tests when compared to wild-type mice.

Transcription factor Egr-1 is required for long-term fear memory and anxiety.

The zinc finger transcription factor Egr-1 is critical for coupling extracellular signals to changes in cellular gene expression. In the hippocampus and amygdala, two major central regions for memory formation and storage, Egr-1 is up-regulated by long-term potentiation (LTP) and learning paradigms. Using Egr-1 knockout mice, we showed that Egr-1 was selectively required for late auditory fear memory while short term, trace and contextual memory were not affected.

Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome.

Trace fear memory requires the activity of the anterior cingulate cortex (ACC) and is sensitive to attention-distracting stimuli. Fragile X syndrome is the most common form of mental retardation with many patients exhibiting attention deficits. Previous studies in fragile X mental retardation 1 (FMR1) knock-out (KO) mice, a mouse model for fragile X, focused mainly on hippocampal-dependent plasticity and spatial memory.

A new assay of thermal-based avoidance test in freely moving mice.

Unlabelled: The hot plate test is a standard way to measure nociceptive response latencies to a noxious thermal stimulus. Here we have modified the classic hot plate by allowing animals to escape to an adjacent chamber after exposure to the heated surface. In this test, the animals escape to the adjacent chamber after exposure to the hot plate set at 50 degrees C.

Kainate receptor-mediated synaptic transmission in the adult anterior cingulate cortex.

Kainate (KA) receptors are expressed widely in the CNS. However, little is known about their functional characterization, molecular identity, and role in synaptic transmission in the forebrain of adult mice. Patch-clamp recordings in genetically modified mice show that postsynaptic KA receptors contribute to fast synaptic transmission in pyramidal neurons in the anterior cingulate cortex (ACC), a forebrain region critical for higher-order cognitive brain functions such as memory and mental disorders.

Pavlovian fear memory induced by activation in the anterior cingulate cortex.

Identifying higher brain central region(s) that are responsible for the unpleasantness of pain is the focus of many recent studies. Here we show that direct stimulation of the anterior cingulate cortex (ACC) in mice produced fear-like freezing responses and induced long-term fear memory, including contextual and auditory fear memory. Auditory fear memory required the activation of N-methyl-D-aspartate (NMDA) receptors in the amygdala.

Contribution of CaMKIV to injury and fear-induced ultrasonic vocalizations in adult mice.

Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that activates the transcription factor CREB. Our previous work demonstrated that mice lacking CaMKIV had a defect in fear memory while behavioral responses to noxious stimuli were unchanged. Here, we measured ultrasonic vocalizations (USVs) before and after fear conditioning and in response to a noxious injection of capsaicin to measure behavioral responses to emotional stimuli.

Altered behavioral responses to noxious stimuli and fear in glutamate receptor 5 (GluR5)- or GluR6-deficient mice.

Different kainate receptor (KAR) subtypes contribute to the regulation of both excitatory and inhibitory transmission. However, no study has reported a role for KAR subtypes in behavioral responses to persistent pain and fear memory. Here we show that responses to capsaicin or inflammatory pain were significantly reduced in mice lacking glutamate receptor 5 (GluR5) but not GluR6 subunits.

Selective contribution of Egr1 (zif/268) to persistent inflammatory pain.

Unlabelled: The zinc finger transcription factor Egr1 is critical for coupling extracellular signals to changes in cellular gene expression. Expression of Egr1, as well as other immediate early genes, is up-regulated in response to a number of noxious stimuli. Activity-dependent activation of Egr1 has been reported in forebrain regions, including the anterior cingulate cortex (ACC), after peripheral injury.

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.

Comparative analysis of the Bradyrhizobium japonicum sucA region.

To study the adjustments made to the tricarboxylic acid cycle during symbiosis of nitrogen-fixing rhizobia with their host legumes, we have characterized the genes encoding the alpha-ketoglutarate dehydrogenase enzyme complex in Bradyrhizobium japonicum. The genes were arranged in the order sucA-sucB-scdA-lpdA, where scdArepresents a short-chain dehydrogenase gene (GenBank accession No. AY049030).