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Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn.

Géranton SM, Fratto V, Tochiki KK, Hunt SP - Mol Pain (2008)

Bottom Line: Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively.Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA.We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell and Developmental Biology, University College London, Medawar Building, London, UK. ucgasmg@ucl.ac.uk

ABSTRACT

Background: Regulation of pain states is, in part, dependent upon plastic changes in neurones within the superficial dorsal horn. There is also compelling evidence that pain states are under the control of descending projections from the brainstem. While a number of transcription factors including Methyl-CpG-binding protein 2 (MeCP2), Zif268 and Fos have been implicated in the regulation of dorsal horn neurone sensitization following injury, modulation of their activity by descending controls has not been investigated.

Results: Here, we describe how descending controls regulate MeCP2 phosphorylation (P-MeCP2), known to relieve transcriptional repression by MeCP2, and Zif268 and Fos expression in the rat superficial dorsal horn, after CFA injection into the hind paw. First, we report that CFA significantly increased P-MeCP2 in Lamina I and II, from 30 min post injection, with a maximum reached after 1 h. The increase in P-MeCP2 paralleled that of Zif268 and Fos, and P-MeCP2 was expressed in large sub-populations of Zif268 and Fos expressing neurones. Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively. Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA.

Conclusion: We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.

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5,7-DHT treatment reduces CFA-induced P-MeCP2, Zif268 and Fos expression. Seven days after 5,7-DHT or saline treatment, animals received CFA and were sacrificed after 1 h. A/ P-MeCP2, Zif268 and Fos expression 1 h after CFA injection in the hind paw were significantly reduced by 5,7-DHT. N = 4/6 in each group. Data show mean ± standard error of the mean; *P < 0.05, ***P < 0.0001. B/ Pictures show typical P-MeCP2 immunoreactivity in the dorsal horn, ipsilateral to the injection, 1 h after CFA injection in the hind paw. 5,7-DHT reduced P-MeCP2 immunoreactivity compared to saline, especially in the medial area of the superficial dorsal horn. Scale bars, 40 μm.
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Figure 7: 5,7-DHT treatment reduces CFA-induced P-MeCP2, Zif268 and Fos expression. Seven days after 5,7-DHT or saline treatment, animals received CFA and were sacrificed after 1 h. A/ P-MeCP2, Zif268 and Fos expression 1 h after CFA injection in the hind paw were significantly reduced by 5,7-DHT. N = 4/6 in each group. Data show mean ± standard error of the mean; *P < 0.05, ***P < 0.0001. B/ Pictures show typical P-MeCP2 immunoreactivity in the dorsal horn, ipsilateral to the injection, 1 h after CFA injection in the hind paw. 5,7-DHT reduced P-MeCP2 immunoreactivity compared to saline, especially in the medial area of the superficial dorsal horn. Scale bars, 40 μm.

Mentions: Animals were separated in to 2 groups, one receiving an intrathecal injection of saline and the other of 5,7-DHT (N = 4/6 in each group). Seven days later, animals received CFA and were sacrificed after 1 h. 5-HT staining showed complete depletion of 5-HT in the superficial dorsal horn after 5,7-DHT, and GFAP and NeuN staining indicated that 5,7-DHT did not cause glial proliferation or hypertrophy or abnormal cell death (Figure 6). When animals received 5,7-DHT, there was a significant reduction compared with saline in expression of P-MeCP2 ipsilateral to the CFA injection (47 ± 4 vs 20 ± 2 immunopositive nuclei; F1,10 = 37, P < 0.001), Zif268 (121 ± 14 vs 76 ± 7; F1,10 = 11, P < 0.05) and Fos (81 ± 7 vs 59 ± 5; F1,10 = 8, P < 0.05) in laminae I-II (Figure 7A and 7B).


Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn.

Géranton SM, Fratto V, Tochiki KK, Hunt SP - Mol Pain (2008)

5,7-DHT treatment reduces CFA-induced P-MeCP2, Zif268 and Fos expression. Seven days after 5,7-DHT or saline treatment, animals received CFA and were sacrificed after 1 h. A/ P-MeCP2, Zif268 and Fos expression 1 h after CFA injection in the hind paw were significantly reduced by 5,7-DHT. N = 4/6 in each group. Data show mean ± standard error of the mean; *P < 0.05, ***P < 0.0001. B/ Pictures show typical P-MeCP2 immunoreactivity in the dorsal horn, ipsilateral to the injection, 1 h after CFA injection in the hind paw. 5,7-DHT reduced P-MeCP2 immunoreactivity compared to saline, especially in the medial area of the superficial dorsal horn. Scale bars, 40 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2553762&req=5

Figure 7: 5,7-DHT treatment reduces CFA-induced P-MeCP2, Zif268 and Fos expression. Seven days after 5,7-DHT or saline treatment, animals received CFA and were sacrificed after 1 h. A/ P-MeCP2, Zif268 and Fos expression 1 h after CFA injection in the hind paw were significantly reduced by 5,7-DHT. N = 4/6 in each group. Data show mean ± standard error of the mean; *P < 0.05, ***P < 0.0001. B/ Pictures show typical P-MeCP2 immunoreactivity in the dorsal horn, ipsilateral to the injection, 1 h after CFA injection in the hind paw. 5,7-DHT reduced P-MeCP2 immunoreactivity compared to saline, especially in the medial area of the superficial dorsal horn. Scale bars, 40 μm.
Mentions: Animals were separated in to 2 groups, one receiving an intrathecal injection of saline and the other of 5,7-DHT (N = 4/6 in each group). Seven days later, animals received CFA and were sacrificed after 1 h. 5-HT staining showed complete depletion of 5-HT in the superficial dorsal horn after 5,7-DHT, and GFAP and NeuN staining indicated that 5,7-DHT did not cause glial proliferation or hypertrophy or abnormal cell death (Figure 6). When animals received 5,7-DHT, there was a significant reduction compared with saline in expression of P-MeCP2 ipsilateral to the CFA injection (47 ± 4 vs 20 ± 2 immunopositive nuclei; F1,10 = 37, P < 0.001), Zif268 (121 ± 14 vs 76 ± 7; F1,10 = 11, P < 0.05) and Fos (81 ± 7 vs 59 ± 5; F1,10 = 8, P < 0.05) in laminae I-II (Figure 7A and 7B).

Bottom Line: Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively.Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA.We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell and Developmental Biology, University College London, Medawar Building, London, UK. ucgasmg@ucl.ac.uk

ABSTRACT

Background: Regulation of pain states is, in part, dependent upon plastic changes in neurones within the superficial dorsal horn. There is also compelling evidence that pain states are under the control of descending projections from the brainstem. While a number of transcription factors including Methyl-CpG-binding protein 2 (MeCP2), Zif268 and Fos have been implicated in the regulation of dorsal horn neurone sensitization following injury, modulation of their activity by descending controls has not been investigated.

Results: Here, we describe how descending controls regulate MeCP2 phosphorylation (P-MeCP2), known to relieve transcriptional repression by MeCP2, and Zif268 and Fos expression in the rat superficial dorsal horn, after CFA injection into the hind paw. First, we report that CFA significantly increased P-MeCP2 in Lamina I and II, from 30 min post injection, with a maximum reached after 1 h. The increase in P-MeCP2 paralleled that of Zif268 and Fos, and P-MeCP2 was expressed in large sub-populations of Zif268 and Fos expressing neurones. Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively. Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA.

Conclusion: We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.

Show MeSH
Related in: MedlinePlus