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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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Related in: MedlinePlus

Enhancement of EPSCs by octopamine in transgenic but not WT mice. (A) Sample traces showing EPSCs before and after application of octopamine (50 μM) in Ap oa1 mice. (B) The time course of octopamine's effect on EPSCs in a neuron shown in A. (C) Pooled data showing octopamine significantly increased EPSCs in transgenic but not WT mice.
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Figure 3: Enhancement of EPSCs by octopamine in transgenic but not WT mice. (A) Sample traces showing EPSCs before and after application of octopamine (50 μM) in Ap oa1 mice. (B) The time course of octopamine's effect on EPSCs in a neuron shown in A. (C) Pooled data showing octopamine significantly increased EPSCs in transgenic but not WT mice.

Mentions: It is well known that Ap oa1 is selectively coupled to Gs protein [38] and activation of heterologous expression of Ap oa1 in HEK293 cells selectively stimulated cAMP synthesis after octopamine application [32]. Next, we wanted to test the function of exogenous Ap oa1 in ACC pyramidal neurons in transgenic mice. AMPA EPSCs were isolated and octopamine (50 μM) was then bath applied after stable EPSCs were obtained. In most neurons tested (8 of 11 neurons/8 mice), octopamine significantly increased the amplitude of EPSCs 10 minutes after the drug application (127.5 ± 6.8% of control, n = 11, P < 0.01, Figure 3A–C). The enhanced EPSCs by octopamine is long lasting, only showing partial recovery after 10 minutes washout of octopamine. In the WT mice, however, octopamine had no significant effect on the amplitude of EPSCs (96.5 ± 5.2% of control, n = 5, P = 0.57, Figure 3C). Therefore, octopamine exerts their stimulatory effect on glutamatergic neurotransmission via octopamine receptors in the transgenic mice.


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)

Enhancement of EPSCs by octopamine in transgenic but not WT mice. (A) Sample traces showing EPSCs before and after application of octopamine (50 μM) in Ap oa1 mice. (B) The time course of octopamine's effect on EPSCs in a neuron shown in A. (C) Pooled data showing octopamine significantly increased EPSCs in transgenic but not WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Enhancement of EPSCs by octopamine in transgenic but not WT mice. (A) Sample traces showing EPSCs before and after application of octopamine (50 μM) in Ap oa1 mice. (B) The time course of octopamine's effect on EPSCs in a neuron shown in A. (C) Pooled data showing octopamine significantly increased EPSCs in transgenic but not WT mice.
Mentions: It is well known that Ap oa1 is selectively coupled to Gs protein [38] and activation of heterologous expression of Ap oa1 in HEK293 cells selectively stimulated cAMP synthesis after octopamine application [32]. Next, we wanted to test the function of exogenous Ap oa1 in ACC pyramidal neurons in transgenic mice. AMPA EPSCs were isolated and octopamine (50 μM) was then bath applied after stable EPSCs were obtained. In most neurons tested (8 of 11 neurons/8 mice), octopamine significantly increased the amplitude of EPSCs 10 minutes after the drug application (127.5 ± 6.8% of control, n = 11, P < 0.01, Figure 3A–C). The enhanced EPSCs by octopamine is long lasting, only showing partial recovery after 10 minutes washout of octopamine. In the WT mice, however, octopamine had no significant effect on the amplitude of EPSCs (96.5 ± 5.2% of control, n = 5, P = 0.57, Figure 3C). Therefore, octopamine exerts their stimulatory effect on glutamatergic neurotransmission via octopamine receptors in the transgenic mice.

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