Intrathecal injection of the ς1 receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain

Dae Hyun Roh, Hyun Woo Kim, Seo Yeon Yoon, Hyoung Sig Seo, Young Bae Kwon, Kee Won Kim, Ho Jae Han, Alvin J. Beitz, Heung Sik Na, Jang Hern Lee

Research output: Contribution to journalArticle

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Abstract

BACKGROUND:: Selective blockade of spinal ς1 receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. METHODS:: Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. RESULTS:: BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation. CONCLUSIONS:: These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.

Original languageEnglish
Pages (from-to)879-889
Number of pages11
JournalAnesthesiology
Volume109
Issue number5
DOIs
Publication statusPublished - 2008 Nov 1

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Spinal Injections
Hyperalgesia
Neuralgia
Constriction
Rodentia
Wounds and Injuries
Maintenance
Phosphorylation
Therapeutic Uses
Sciatic Nerve
Pain Measurement
Chronic Pain
Western Blotting
Immunohistochemistry
BD 1047
aspartic acid receptor

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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Intrathecal injection of the ς1 receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain. / Roh, Dae Hyun; Kim, Hyun Woo; Yoon, Seo Yeon; Seo, Hyoung Sig; Kwon, Young Bae; Kim, Kee Won; Han, Ho Jae; Beitz, Alvin J.; Na, Heung Sik; Lee, Jang Hern.

In: Anesthesiology, Vol. 109, No. 5, 01.11.2008, p. 879-889.

Research output: Contribution to journalArticle

Roh, Dae Hyun ; Kim, Hyun Woo ; Yoon, Seo Yeon ; Seo, Hyoung Sig ; Kwon, Young Bae ; Kim, Kee Won ; Han, Ho Jae ; Beitz, Alvin J. ; Na, Heung Sik ; Lee, Jang Hern. / Intrathecal injection of the ς1 receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain. In: Anesthesiology. 2008 ; Vol. 109, No. 5. pp. 879-889.
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abstract = "BACKGROUND:: Selective blockade of spinal ς1 receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. METHODS:: Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. RESULTS:: BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation. CONCLUSIONS:: These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.",
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T1 - Intrathecal injection of the ς1 receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain

AU - Roh, Dae Hyun

AU - Kim, Hyun Woo

AU - Yoon, Seo Yeon

AU - Seo, Hyoung Sig

AU - Kwon, Young Bae

AU - Kim, Kee Won

AU - Han, Ho Jae

AU - Beitz, Alvin J.

AU - Na, Heung Sik

AU - Lee, Jang Hern

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N2 - BACKGROUND:: Selective blockade of spinal ς1 receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. METHODS:: Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. RESULTS:: BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation. CONCLUSIONS:: These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.

AB - BACKGROUND:: Selective blockade of spinal ς1 receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. METHODS:: Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. RESULTS:: BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-d-aspartate receptor subunit 1 expression and phosphorylation. CONCLUSIONS:: These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.

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