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Involvement of phosphatase and tensin homolog deleted from chromosome 10 in rodent model of neuropathic pain.

Huang SY, Sung CS, Chen WF, Chen CH, Feng CW, Yang SN, Hung HC, Chen NF, Lin PR, Chen SC, Wang HM, Chu TH, Tai MH, Wen ZH - J Neuroinflammation (2015)

Bottom Line: There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain.These data indicate the importance of downregulation of spinal PTEN for nociception.Furthermore, upregulation of spinal PTEN by i.t.

View Article: PubMed Central - PubMed

Affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, No. 70, Lienhai Road, Kaohsiung, 80424, Taiwan. johnjohnkings@gmail.com.

ABSTRACT

Background: Many cancer research studies have extensively examined the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathway. There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain. Here, we report a role for PTEN in a rodent model of neuropathic pain.

Results: We found that chronic constriction injury (CCI) surgery in rats could elicit downregulation of spinal PTEN as well as upregulation of phosphorylated PTEN (phospho-PTEN) and phosphorylated mammalian target of rapamycin (phospho-mTOR). After examining such changes in endogenous PTEN in neuropathic rats, we explored the effects of modulating the spinal PTEN pathway on nociceptive behaviors. The normal rats exhibited mechanical allodynia after intrathecal (i.t.) injection of adenovirus-mediated PTEN antisense oligonucleotide (Ad-antisense PTEN). These data indicate the importance of downregulation of spinal PTEN for nociception. Moreover, upregulation of spinal PTEN by i.t. adenovirus-mediated PTEN (Ad-PTEN) significantly prevented CCI-induced development of nociceptive sensitization, thermal hyperalgesia, mechanical allodynia, cold allodynia, and weight-bearing deficits in neuropathic rats. Furthermore, upregulation of spinal PTEN by i.t. Ad-PTEN significantly attenuated CCI-induced microglia and astrocyte activation, upregulation of tumor necrosis factor-α (TNF-α) and phospho-mTOR, and downregulation of PTEN in neuropathic rats 14 days post injury.

Conclusions: These findings demonstrate that PTEN plays a key, beneficial role in a rodent model of neuropathic pain.

No MeSH data available.


Related in: MedlinePlus

The effects of i.t. Ad-PTEN on CCI-induced microglial and astrocytic activation and upregulation of TNF-α. Spinal cord sections (10 μm) obtained 14 days post-surgery from sham-operated plus i.t. vehicle (A, D, G), CCI plus i.t. Ad-GFP (B, E, H), and CCI plus i.t. Ad-PTEN (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (red; (A-C)) and GFAP (red; (D-F)), TNF-α (red; (G-I)) in the spinal cord. Quantification of OX-42 (J) and GFAP (K), and TNF-α (L) immunoreactivity in the ipsilateral dorsal horn of the lumbar spinal gray matter. Ad-GFP, adenovirus-mediated green fluorescent protein; Ad-PTEN, adenovirus-mediated phosphatase and tensin homolog deleted from chromosome 10; CCI, chronic constriction injury; GFAP, glial fibrillary acidic protein; TNF, tumor necrosis factor. Each bar in (J-L) represents the mean ± SEM with six rats per group. Ad-PTEN (i.t.) significantly inhibited CCI-induced upregulation of spinal OX-42, GFAP, and TNF-α immunoreactivity. Scale bars: 200 μm for all images (A-I). *P < 0.05 compared with sham-operated plus i.t. vehicle group; #P < 0.05 compared with CCI plus i.t. Ad-GFP.
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Fig7: The effects of i.t. Ad-PTEN on CCI-induced microglial and astrocytic activation and upregulation of TNF-α. Spinal cord sections (10 μm) obtained 14 days post-surgery from sham-operated plus i.t. vehicle (A, D, G), CCI plus i.t. Ad-GFP (B, E, H), and CCI plus i.t. Ad-PTEN (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (red; (A-C)) and GFAP (red; (D-F)), TNF-α (red; (G-I)) in the spinal cord. Quantification of OX-42 (J) and GFAP (K), and TNF-α (L) immunoreactivity in the ipsilateral dorsal horn of the lumbar spinal gray matter. Ad-GFP, adenovirus-mediated green fluorescent protein; Ad-PTEN, adenovirus-mediated phosphatase and tensin homolog deleted from chromosome 10; CCI, chronic constriction injury; GFAP, glial fibrillary acidic protein; TNF, tumor necrosis factor. Each bar in (J-L) represents the mean ± SEM with six rats per group. Ad-PTEN (i.t.) significantly inhibited CCI-induced upregulation of spinal OX-42, GFAP, and TNF-α immunoreactivity. Scale bars: 200 μm for all images (A-I). *P < 0.05 compared with sham-operated plus i.t. vehicle group; #P < 0.05 compared with CCI plus i.t. Ad-GFP.

Mentions: For spinal immunohistofluorescence assay, we collected spinal tissue on day 14 post injury from the following three groups of rats: (1) sham-operated plus i.t. vehicle, (2) CCI plus i.t. Ad-GFP, and (3) CCI plus i.t. Ad-PTEN. OX-42-, GFAP-, and TNF-α-immunoreactive cells were scattered throughout the ipsilateral dorsal horn of the lumbar spinal gray matter of sham-operated plus i.t. vehicle (Figure 7A,D,G), CCI plus i.t. Ad-GFP (Figure 7B,E,H), and CCI plus i.t. Ad-PTEN (Figure 7C,F,I) groups. Similarly, and as previously reported,[19,22] the immunoreactivity of OX-42 (Figure 7B), GFAP (Figure 7E), and TNF-α (Figure 7H) of CCI plus i.t. Ad-GFP group were upregulated on day 14 post injury when compared with the sham-operated plus i.t. vehicle group. CCI-induced upregulation of OX-42 (Figure 7C), GFAP (Figure 7F), and TNF-α (Figure 7I) were inhibited by i.t. Ad-PTEN. Quantification of OX-42 (Figure 7J), GFAP (Figure 7K), and TNF-α (Figure 7L) immunoreactivity supported the finding that inhibition of CCI-induced upregulation of OX-42 and GFAP, which are microglial and astrocytic immunohistochemical activation markers, as well as TNF-α, are consistent with the anti-nociceptive effects of i.t. Ad-PTEN.Figure 7


Involvement of phosphatase and tensin homolog deleted from chromosome 10 in rodent model of neuropathic pain.

Huang SY, Sung CS, Chen WF, Chen CH, Feng CW, Yang SN, Hung HC, Chen NF, Lin PR, Chen SC, Wang HM, Chu TH, Tai MH, Wen ZH - J Neuroinflammation (2015)

The effects of i.t. Ad-PTEN on CCI-induced microglial and astrocytic activation and upregulation of TNF-α. Spinal cord sections (10 μm) obtained 14 days post-surgery from sham-operated plus i.t. vehicle (A, D, G), CCI plus i.t. Ad-GFP (B, E, H), and CCI plus i.t. Ad-PTEN (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (red; (A-C)) and GFAP (red; (D-F)), TNF-α (red; (G-I)) in the spinal cord. Quantification of OX-42 (J) and GFAP (K), and TNF-α (L) immunoreactivity in the ipsilateral dorsal horn of the lumbar spinal gray matter. Ad-GFP, adenovirus-mediated green fluorescent protein; Ad-PTEN, adenovirus-mediated phosphatase and tensin homolog deleted from chromosome 10; CCI, chronic constriction injury; GFAP, glial fibrillary acidic protein; TNF, tumor necrosis factor. Each bar in (J-L) represents the mean ± SEM with six rats per group. Ad-PTEN (i.t.) significantly inhibited CCI-induced upregulation of spinal OX-42, GFAP, and TNF-α immunoreactivity. Scale bars: 200 μm for all images (A-I). *P < 0.05 compared with sham-operated plus i.t. vehicle group; #P < 0.05 compared with CCI plus i.t. Ad-GFP.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig7: The effects of i.t. Ad-PTEN on CCI-induced microglial and astrocytic activation and upregulation of TNF-α. Spinal cord sections (10 μm) obtained 14 days post-surgery from sham-operated plus i.t. vehicle (A, D, G), CCI plus i.t. Ad-GFP (B, E, H), and CCI plus i.t. Ad-PTEN (C, F, I) groups. Immunostaining images show cells labeled with OX-42 (red; (A-C)) and GFAP (red; (D-F)), TNF-α (red; (G-I)) in the spinal cord. Quantification of OX-42 (J) and GFAP (K), and TNF-α (L) immunoreactivity in the ipsilateral dorsal horn of the lumbar spinal gray matter. Ad-GFP, adenovirus-mediated green fluorescent protein; Ad-PTEN, adenovirus-mediated phosphatase and tensin homolog deleted from chromosome 10; CCI, chronic constriction injury; GFAP, glial fibrillary acidic protein; TNF, tumor necrosis factor. Each bar in (J-L) represents the mean ± SEM with six rats per group. Ad-PTEN (i.t.) significantly inhibited CCI-induced upregulation of spinal OX-42, GFAP, and TNF-α immunoreactivity. Scale bars: 200 μm for all images (A-I). *P < 0.05 compared with sham-operated plus i.t. vehicle group; #P < 0.05 compared with CCI plus i.t. Ad-GFP.
Mentions: For spinal immunohistofluorescence assay, we collected spinal tissue on day 14 post injury from the following three groups of rats: (1) sham-operated plus i.t. vehicle, (2) CCI plus i.t. Ad-GFP, and (3) CCI plus i.t. Ad-PTEN. OX-42-, GFAP-, and TNF-α-immunoreactive cells were scattered throughout the ipsilateral dorsal horn of the lumbar spinal gray matter of sham-operated plus i.t. vehicle (Figure 7A,D,G), CCI plus i.t. Ad-GFP (Figure 7B,E,H), and CCI plus i.t. Ad-PTEN (Figure 7C,F,I) groups. Similarly, and as previously reported,[19,22] the immunoreactivity of OX-42 (Figure 7B), GFAP (Figure 7E), and TNF-α (Figure 7H) of CCI plus i.t. Ad-GFP group were upregulated on day 14 post injury when compared with the sham-operated plus i.t. vehicle group. CCI-induced upregulation of OX-42 (Figure 7C), GFAP (Figure 7F), and TNF-α (Figure 7I) were inhibited by i.t. Ad-PTEN. Quantification of OX-42 (Figure 7J), GFAP (Figure 7K), and TNF-α (Figure 7L) immunoreactivity supported the finding that inhibition of CCI-induced upregulation of OX-42 and GFAP, which are microglial and astrocytic immunohistochemical activation markers, as well as TNF-α, are consistent with the anti-nociceptive effects of i.t. Ad-PTEN.Figure 7

Bottom Line: There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain.These data indicate the importance of downregulation of spinal PTEN for nociception.Furthermore, upregulation of spinal PTEN by i.t.

View Article: PubMed Central - PubMed

Affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, No. 70, Lienhai Road, Kaohsiung, 80424, Taiwan. johnjohnkings@gmail.com.

ABSTRACT

Background: Many cancer research studies have extensively examined the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathway. There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain. Here, we report a role for PTEN in a rodent model of neuropathic pain.

Results: We found that chronic constriction injury (CCI) surgery in rats could elicit downregulation of spinal PTEN as well as upregulation of phosphorylated PTEN (phospho-PTEN) and phosphorylated mammalian target of rapamycin (phospho-mTOR). After examining such changes in endogenous PTEN in neuropathic rats, we explored the effects of modulating the spinal PTEN pathway on nociceptive behaviors. The normal rats exhibited mechanical allodynia after intrathecal (i.t.) injection of adenovirus-mediated PTEN antisense oligonucleotide (Ad-antisense PTEN). These data indicate the importance of downregulation of spinal PTEN for nociception. Moreover, upregulation of spinal PTEN by i.t. adenovirus-mediated PTEN (Ad-PTEN) significantly prevented CCI-induced development of nociceptive sensitization, thermal hyperalgesia, mechanical allodynia, cold allodynia, and weight-bearing deficits in neuropathic rats. Furthermore, upregulation of spinal PTEN by i.t. Ad-PTEN significantly attenuated CCI-induced microglia and astrocyte activation, upregulation of tumor necrosis factor-α (TNF-α) and phospho-mTOR, and downregulation of PTEN in neuropathic rats 14 days post injury.

Conclusions: These findings demonstrate that PTEN plays a key, beneficial role in a rodent model of neuropathic pain.

No MeSH data available.


Related in: MedlinePlus