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Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex.

Wu LJ, Steenland HW, Kim SS, Isiegas C, Abel T, Kaang BK, Zhuo M - Mol Pain (2008)

Bottom Line: We found that activation of Ap oa1 by octopamine enhanced glutamatergic synaptic transmission in the ACC by increasing presynaptic glutamate release in vitro.Bilateral microinjection of octopamine into the ACC significantly facilitated behavioral responses to inflammatory pain but not acute pain.The present study provides the first evidence linking enhanced presynaptic glutamate release in the ACC to behavioral sensitization caused by peripheral inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto Centre for Study of Pain, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. longjun.wu@utoronto.ca

ABSTRACT
Both presynaptic and postsynaptic alterations are associated with plastic changes of brain circuits, such as learning and memory, drug addiction and chronic pain. However, the dissection of the relative contributions of pre- and postsynaptic components to brain functions is difficult. We have previously shown peripheral inflammation caused both presynaptic and postsynaptic changes and calcium-stimulated cyclic AMP (cAMP) pathway in the anterior cingulate cortex (ACC) is critical in the synaptic plasticity and behavioral sensitization to pain. It remains to be elucidated whether presynaptic or postsynaptic modulation by cAMP in the ACC could be sufficient for enhancing inflammatory pain. In order to address this question, we took advantage of a novel transgenic mouse model, heterologously expressing an Aplysia octopamine receptor (Ap oa1). This receptor is G protein-coupled and selectively activates the cAMP pathway. We found that activation of Ap oa1 by octopamine enhanced glutamatergic synaptic transmission in the ACC by increasing presynaptic glutamate release in vitro. Bilateral microinjection of octopamine into the ACC significantly facilitated behavioral responses to inflammatory pain but not acute pain. The present study provides the first evidence linking enhanced presynaptic glutamate release in the ACC to behavioral sensitization caused by peripheral inflammation.

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Proposed model for presynaptic Ap oa1 in the synapse in the ACC from transgenic mice. Diagram showing that activation of presynaptic Ap oa1 leads to the production of cAMP. cAMP-related signaling pathways facilitate the glutamate release from presynaptic terminal. cAMP produced by activation of Ap oa1 in the presynaptic terminal may mimic the effects of cAMP produced by activation of presynaptic calcium-stimulated AC1 [30]. The released glutamate then acts on postsynaptic glutamate receptors, such as AMPA receptors (AMPAR) and NMDA receptors (NMDAR), and trigger the downstream signaling pathways. In the transgenic mice, Ap oa1 is preferentially expressed in the presynaptic terminal in the ACC.
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Figure 7: Proposed model for presynaptic Ap oa1 in the synapse in the ACC from transgenic mice. Diagram showing that activation of presynaptic Ap oa1 leads to the production of cAMP. cAMP-related signaling pathways facilitate the glutamate release from presynaptic terminal. cAMP produced by activation of Ap oa1 in the presynaptic terminal may mimic the effects of cAMP produced by activation of presynaptic calcium-stimulated AC1 [30]. The released glutamate then acts on postsynaptic glutamate receptors, such as AMPA receptors (AMPAR) and NMDA receptors (NMDAR), and trigger the downstream signaling pathways. In the transgenic mice, Ap oa1 is preferentially expressed in the presynaptic terminal in the ACC.

Mentions: In the present study, we used novel transgenic mice heterologously expressing Ap oa1 receptors to examine the role of cAMP pathway in synaptic transmission and chronic pain in the ACC. The use of exogenous receptors is an innovative method that applies the precision of molecular biological techniques to studies on neuronal network. We found that activation of Ap oa1 receptors in the ACC enhanced presynaptic glutamate release (Figure 7) as well as behavioral responses to chronic pain. This is the first attempt to directly address the G protein-coupled cAMP pathway in synaptic transmission and its functional significance in the ACC. Our results suggest that increasing presynaptic glutamate release in the ACC is sufficient for enhanced chronic pain.


Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex.

Wu LJ, Steenland HW, Kim SS, Isiegas C, Abel T, Kaang BK, Zhuo M - Mol Pain (2008)

Proposed model for presynaptic Ap oa1 in the synapse in the ACC from transgenic mice. Diagram showing that activation of presynaptic Ap oa1 leads to the production of cAMP. cAMP-related signaling pathways facilitate the glutamate release from presynaptic terminal. cAMP produced by activation of Ap oa1 in the presynaptic terminal may mimic the effects of cAMP produced by activation of presynaptic calcium-stimulated AC1 [30]. The released glutamate then acts on postsynaptic glutamate receptors, such as AMPA receptors (AMPAR) and NMDA receptors (NMDAR), and trigger the downstream signaling pathways. In the transgenic mice, Ap oa1 is preferentially expressed in the presynaptic terminal in the ACC.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570662&req=5

Figure 7: Proposed model for presynaptic Ap oa1 in the synapse in the ACC from transgenic mice. Diagram showing that activation of presynaptic Ap oa1 leads to the production of cAMP. cAMP-related signaling pathways facilitate the glutamate release from presynaptic terminal. cAMP produced by activation of Ap oa1 in the presynaptic terminal may mimic the effects of cAMP produced by activation of presynaptic calcium-stimulated AC1 [30]. The released glutamate then acts on postsynaptic glutamate receptors, such as AMPA receptors (AMPAR) and NMDA receptors (NMDAR), and trigger the downstream signaling pathways. In the transgenic mice, Ap oa1 is preferentially expressed in the presynaptic terminal in the ACC.
Mentions: In the present study, we used novel transgenic mice heterologously expressing Ap oa1 receptors to examine the role of cAMP pathway in synaptic transmission and chronic pain in the ACC. The use of exogenous receptors is an innovative method that applies the precision of molecular biological techniques to studies on neuronal network. We found that activation of Ap oa1 receptors in the ACC enhanced presynaptic glutamate release (Figure 7) as well as behavioral responses to chronic pain. This is the first attempt to directly address the G protein-coupled cAMP pathway in synaptic transmission and its functional significance in the ACC. Our results suggest that increasing presynaptic glutamate release in the ACC is sufficient for enhanced chronic pain.

Bottom Line: We found that activation of Ap oa1 by octopamine enhanced glutamatergic synaptic transmission in the ACC by increasing presynaptic glutamate release in vitro.Bilateral microinjection of octopamine into the ACC significantly facilitated behavioral responses to inflammatory pain but not acute pain.The present study provides the first evidence linking enhanced presynaptic glutamate release in the ACC to behavioral sensitization caused by peripheral inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology, Faculty of Medicine, University of Toronto Centre for Study of Pain, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. longjun.wu@utoronto.ca

ABSTRACT
Both presynaptic and postsynaptic alterations are associated with plastic changes of brain circuits, such as learning and memory, drug addiction and chronic pain. However, the dissection of the relative contributions of pre- and postsynaptic components to brain functions is difficult. We have previously shown peripheral inflammation caused both presynaptic and postsynaptic changes and calcium-stimulated cyclic AMP (cAMP) pathway in the anterior cingulate cortex (ACC) is critical in the synaptic plasticity and behavioral sensitization to pain. It remains to be elucidated whether presynaptic or postsynaptic modulation by cAMP in the ACC could be sufficient for enhancing inflammatory pain. In order to address this question, we took advantage of a novel transgenic mouse model, heterologously expressing an Aplysia octopamine receptor (Ap oa1). This receptor is G protein-coupled and selectively activates the cAMP pathway. We found that activation of Ap oa1 by octopamine enhanced glutamatergic synaptic transmission in the ACC by increasing presynaptic glutamate release in vitro. Bilateral microinjection of octopamine into the ACC significantly facilitated behavioral responses to inflammatory pain but not acute pain. The present study provides the first evidence linking enhanced presynaptic glutamate release in the ACC to behavioral sensitization caused by peripheral inflammation.

Show MeSH
Related in: MedlinePlus