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ATP-sensitive potassium channels alleviate postoperative pain through JNK-dependent MCP-1 expression in spinal cord.

Zhu X, Liu J, Gao Y, Cao S, Shen S - Int. J. Mol. Med. (2015)

Bottom Line: The results showed that KATP channel subunits Kir6.1, SUR1 and SUR2 were normally expressed in the spinal cord and significantly downregulated after SMIR.Furthermore, in vitro studies showed that following incubation with LPS, the astrocytic MCP-1 mRNA expression and p-JNK content were markedly increased, whereas the mRNA levels of Kir6.1 and SUR2 were significantly downregulated in astrocytes.The results suggested that KATP channel opener treatment is an effective therapy for postoperative pain in animals, through the activation of the JNK/MCP-1 pathway in astrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.

ABSTRACT
Although adenosine triphosphate-sensitive potassium (KATP) channels have been proven to be involved in regulating postoperative pain, the underlying mechanism remains to be investigated. In this study, we aimed to determine the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat pain model, in which rats were subjected to skin/muscle incision and retraction (SMIR) surgery, as well as in LPS-stimulated astrocytes. The results showed that KATP channel subunits Kir6.1, SUR1 and SUR2 were normally expressed in the spinal cord and significantly downregulated after SMIR. SMIR caused a marked increase in monocyte chemoattractant protein-1 (MCP-1) mRNA expression and in the protein level of p-JNK in the spinal cord. Intrathecal administration of a KATP channel opener pinacidil (Pina) suppressed mechanical allodynia after SMIR and significantly downregulated the MCP-1 mRNA expression and the protein level of p-JNK induced by SMIR. Inverted fluorescence microscopy showed that Kir6.1 was co-localized with astrocytes only and SUR2 was co-localized primarily with neurons, in a small amount with astrocytes. Furthermore, in vitro studies showed that following incubation with LPS, the astrocytic MCP-1 mRNA expression and p-JNK content were markedly increased, whereas the mRNA levels of Kir6.1 and SUR2 were significantly downregulated in astrocytes. KATP channel opener pinacidil inhibited the LPS-triggered MCP-1 and p-JNK elevation in rat primary astrocytes. The results suggested that KATP channel opener treatment is an effective therapy for postoperative pain in animals, through the activation of the JNK/MCP-1 pathway in astrocytes.

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Decrease of KATP channel subunits and increase of MCP-1 and JNK expression after SMIR in the spinal cord KATP channel subunits. (A–D) mRNA expression of KATP channel subunits. (E–G) Protein expression of KATP channel subunits. (H) mRNA expression of MCP-1. (I) Protein expression of JNK. *P≤0.05, **P≤0.01, ***P≤0.001 vs. normal. KATP, adenosine triphosphate-sensitive potassium; MCP-1, monocyte chemoattractant protein-1; SMIR, skin/muscle incision and retraction.
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f2-ijmm-35-05-1257: Decrease of KATP channel subunits and increase of MCP-1 and JNK expression after SMIR in the spinal cord KATP channel subunits. (A–D) mRNA expression of KATP channel subunits. (E–G) Protein expression of KATP channel subunits. (H) mRNA expression of MCP-1. (I) Protein expression of JNK. *P≤0.05, **P≤0.01, ***P≤0.001 vs. normal. KATP, adenosine triphosphate-sensitive potassium; MCP-1, monocyte chemoattractant protein-1; SMIR, skin/muscle incision and retraction.

Mentions: To determine whether KATP plays a role during the development of postoperative pain, we first performed a time-course analysis of the subunits of KATP expression in the spinal cord after the SMIR operations. The results showed that compared with normal rats, SMIR caused a significant decrease in the expression of the KATP channel subunits Kir6.1 (Fig. 2A), Kir6.2 (Fig. 2B) and SUR2 (Fig. 2D) on postoperative day 7 (P<0.05, Fig. 2). However, from days 3 to 7 after SMIR, no significant variation of SUR1 mRNA expression was observed compared with the normal rats (P>0.05, Fig. 2C). The ressults from western blot analysis revealed that the expression of the KATP channel subunits Kir6.1 (Fig. 2E) and SUR2 (Fig. 2E) in the spinal cord was significantly decreased at 3 and 7 days after SMIR (P<0.05). SUR1 expression was reduced at post-operative day 3, but returned to the level of the control at post-operative day 7 (Fig. 2F), indicating it may not be important for pain hypersensitivity. The protein expression for Kir6.2 subunit was extremely low and not detectable in the spinal cord. By contrast, the PCR results showed that MCP-1 expression in the spinal cord was significantly increased at 3 and 7 days (P<0.01) after SMIR (Fig. 2H).


ATP-sensitive potassium channels alleviate postoperative pain through JNK-dependent MCP-1 expression in spinal cord.

Zhu X, Liu J, Gao Y, Cao S, Shen S - Int. J. Mol. Med. (2015)

Decrease of KATP channel subunits and increase of MCP-1 and JNK expression after SMIR in the spinal cord KATP channel subunits. (A–D) mRNA expression of KATP channel subunits. (E–G) Protein expression of KATP channel subunits. (H) mRNA expression of MCP-1. (I) Protein expression of JNK. *P≤0.05, **P≤0.01, ***P≤0.001 vs. normal. KATP, adenosine triphosphate-sensitive potassium; MCP-1, monocyte chemoattractant protein-1; SMIR, skin/muscle incision and retraction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380206&req=5

f2-ijmm-35-05-1257: Decrease of KATP channel subunits and increase of MCP-1 and JNK expression after SMIR in the spinal cord KATP channel subunits. (A–D) mRNA expression of KATP channel subunits. (E–G) Protein expression of KATP channel subunits. (H) mRNA expression of MCP-1. (I) Protein expression of JNK. *P≤0.05, **P≤0.01, ***P≤0.001 vs. normal. KATP, adenosine triphosphate-sensitive potassium; MCP-1, monocyte chemoattractant protein-1; SMIR, skin/muscle incision and retraction.
Mentions: To determine whether KATP plays a role during the development of postoperative pain, we first performed a time-course analysis of the subunits of KATP expression in the spinal cord after the SMIR operations. The results showed that compared with normal rats, SMIR caused a significant decrease in the expression of the KATP channel subunits Kir6.1 (Fig. 2A), Kir6.2 (Fig. 2B) and SUR2 (Fig. 2D) on postoperative day 7 (P<0.05, Fig. 2). However, from days 3 to 7 after SMIR, no significant variation of SUR1 mRNA expression was observed compared with the normal rats (P>0.05, Fig. 2C). The ressults from western blot analysis revealed that the expression of the KATP channel subunits Kir6.1 (Fig. 2E) and SUR2 (Fig. 2E) in the spinal cord was significantly decreased at 3 and 7 days after SMIR (P<0.05). SUR1 expression was reduced at post-operative day 3, but returned to the level of the control at post-operative day 7 (Fig. 2F), indicating it may not be important for pain hypersensitivity. The protein expression for Kir6.2 subunit was extremely low and not detectable in the spinal cord. By contrast, the PCR results showed that MCP-1 expression in the spinal cord was significantly increased at 3 and 7 days (P<0.01) after SMIR (Fig. 2H).

Bottom Line: The results showed that KATP channel subunits Kir6.1, SUR1 and SUR2 were normally expressed in the spinal cord and significantly downregulated after SMIR.Furthermore, in vitro studies showed that following incubation with LPS, the astrocytic MCP-1 mRNA expression and p-JNK content were markedly increased, whereas the mRNA levels of Kir6.1 and SUR2 were significantly downregulated in astrocytes.The results suggested that KATP channel opener treatment is an effective therapy for postoperative pain in animals, through the activation of the JNK/MCP-1 pathway in astrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.

ABSTRACT
Although adenosine triphosphate-sensitive potassium (KATP) channels have been proven to be involved in regulating postoperative pain, the underlying mechanism remains to be investigated. In this study, we aimed to determine the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat pain model, in which rats were subjected to skin/muscle incision and retraction (SMIR) surgery, as well as in LPS-stimulated astrocytes. The results showed that KATP channel subunits Kir6.1, SUR1 and SUR2 were normally expressed in the spinal cord and significantly downregulated after SMIR. SMIR caused a marked increase in monocyte chemoattractant protein-1 (MCP-1) mRNA expression and in the protein level of p-JNK in the spinal cord. Intrathecal administration of a KATP channel opener pinacidil (Pina) suppressed mechanical allodynia after SMIR and significantly downregulated the MCP-1 mRNA expression and the protein level of p-JNK induced by SMIR. Inverted fluorescence microscopy showed that Kir6.1 was co-localized with astrocytes only and SUR2 was co-localized primarily with neurons, in a small amount with astrocytes. Furthermore, in vitro studies showed that following incubation with LPS, the astrocytic MCP-1 mRNA expression and p-JNK content were markedly increased, whereas the mRNA levels of Kir6.1 and SUR2 were significantly downregulated in astrocytes. KATP channel opener pinacidil inhibited the LPS-triggered MCP-1 and p-JNK elevation in rat primary astrocytes. The results suggested that KATP channel opener treatment is an effective therapy for postoperative pain in animals, through the activation of the JNK/MCP-1 pathway in astrocytes.

Show MeSH
Related in: MedlinePlus