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Plasticity-Related PKMζ Signaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury.

Han J, Kwon M, Cha M, Tanioka M, Hong SK, Bai SJ, Lee BH - Neural Plast. (2015)

Bottom Line: Mechanical allodynia was significantly decreased by ZIP microinjection into the IC.The analgesic effect lasted for 12 hours.These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea ; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.

ABSTRACT
The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ (PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζ in the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. After ζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ (p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζ were decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain.

No MeSH data available.


Related in: MedlinePlus

Fluorescence images of zif268 expression in the IC of nerve-injured and sham groups. (a) The sham group showed little expression of zif268-positive cells, unlike the nerve-injured group. (b) NeuN, a neuronal marker (red), was expressed in the sham group. (c) Colocalization of zif268 (green) and NeuN (red) is observed in the sham group. (d) In the nerve-injured group, the distribution of zif268 expression (green) was denser than in the sham group. (e) As in (b), NeuN was expressed in the nerve-injured group. (f) As in (c), colocalization of zif268 (green) and NeuN (red) is observed in the nerve-injured group. Scale bar, 50 μm.
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fig2: Fluorescence images of zif268 expression in the IC of nerve-injured and sham groups. (a) The sham group showed little expression of zif268-positive cells, unlike the nerve-injured group. (b) NeuN, a neuronal marker (red), was expressed in the sham group. (c) Colocalization of zif268 (green) and NeuN (red) is observed in the sham group. (d) In the nerve-injured group, the distribution of zif268 expression (green) was denser than in the sham group. (e) As in (b), NeuN was expressed in the nerve-injured group. (f) As in (c), colocalization of zif268 (green) and NeuN (red) is observed in the nerve-injured group. Scale bar, 50 μm.

Mentions: To confirm that zif268 was co-labeled with NeuN in the IC, double labeling of zif268 and NeuN was performed. The representative images of the nerve-injured group are shown in Figures 2(d), 2(e), and 2(f), and those of the sham group are shown in Figures 2(a), 2(b), and 2(c). Zif268 immunoreactivity (green) was observed in the IC (Figures 2(a) and 2(d)). NeuN, a neuronal marker (red), was observed in the IC (Figures 2(b) and 2(e)). Colocalization of zif268 (green) and NeuN (red) was detected in the IC (Figures 2(c) and 2(f)). As shown in Figure 2, zif268-positive cells were colocalized with NeuN-positive cells. This result indicates that zif268 is expressed in IC neurons. Nerve-injured rats have more zif268-positive cells (Figure 2(d)) than the sham group rats (Figure 2(a)). The number of NeuN-positive cells in the IC is similar between the nerve-injured (Figure 2(e)) and sham-operated groups (Figure 2(b)). The merged data of zif268 and NeuN expression show that the IC has a relationship with neuropathic pain (Figures 2(c) and 2(f)).


Plasticity-Related PKMζ Signaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury.

Han J, Kwon M, Cha M, Tanioka M, Hong SK, Bai SJ, Lee BH - Neural Plast. (2015)

Fluorescence images of zif268 expression in the IC of nerve-injured and sham groups. (a) The sham group showed little expression of zif268-positive cells, unlike the nerve-injured group. (b) NeuN, a neuronal marker (red), was expressed in the sham group. (c) Colocalization of zif268 (green) and NeuN (red) is observed in the sham group. (d) In the nerve-injured group, the distribution of zif268 expression (green) was denser than in the sham group. (e) As in (b), NeuN was expressed in the nerve-injured group. (f) As in (c), colocalization of zif268 (green) and NeuN (red) is observed in the nerve-injured group. Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4592717&req=5

fig2: Fluorescence images of zif268 expression in the IC of nerve-injured and sham groups. (a) The sham group showed little expression of zif268-positive cells, unlike the nerve-injured group. (b) NeuN, a neuronal marker (red), was expressed in the sham group. (c) Colocalization of zif268 (green) and NeuN (red) is observed in the sham group. (d) In the nerve-injured group, the distribution of zif268 expression (green) was denser than in the sham group. (e) As in (b), NeuN was expressed in the nerve-injured group. (f) As in (c), colocalization of zif268 (green) and NeuN (red) is observed in the nerve-injured group. Scale bar, 50 μm.
Mentions: To confirm that zif268 was co-labeled with NeuN in the IC, double labeling of zif268 and NeuN was performed. The representative images of the nerve-injured group are shown in Figures 2(d), 2(e), and 2(f), and those of the sham group are shown in Figures 2(a), 2(b), and 2(c). Zif268 immunoreactivity (green) was observed in the IC (Figures 2(a) and 2(d)). NeuN, a neuronal marker (red), was observed in the IC (Figures 2(b) and 2(e)). Colocalization of zif268 (green) and NeuN (red) was detected in the IC (Figures 2(c) and 2(f)). As shown in Figure 2, zif268-positive cells were colocalized with NeuN-positive cells. This result indicates that zif268 is expressed in IC neurons. Nerve-injured rats have more zif268-positive cells (Figure 2(d)) than the sham group rats (Figure 2(a)). The number of NeuN-positive cells in the IC is similar between the nerve-injured (Figure 2(e)) and sham-operated groups (Figure 2(b)). The merged data of zif268 and NeuN expression show that the IC has a relationship with neuropathic pain (Figures 2(c) and 2(f)).

Bottom Line: Mechanical allodynia was significantly decreased by ZIP microinjection into the IC.The analgesic effect lasted for 12 hours.These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea ; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.

ABSTRACT
The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ (PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζ in the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. After ζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ (p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζ were decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain.

No MeSH data available.


Related in: MedlinePlus