The opioid antagonist, β-funaltrexamine, inhibits chemokine expression in human astroglial cells

Randall Davis, Daniel J. Buck, Neda Saffarian, Craig Stevens

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)α induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-κB], we determined that NF-κB activation is instrumental in TNFα-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFα stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFα-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor β-funaltrexamine (β-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFα-induced CXCL10 expression. Rather, β-FNA dose-dependently inhibited TNFα-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and β-FNA each reduced TNFα-induced nuclear translocation of NF-κB p65. These data show that β-FNA and fentanyl inhibit TNFα-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFα-induced CXCL10 expression by fentanyl and β-FNA is not directly related to a reduction in NF-κB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, β-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
JournalJournal of Neuroimmunology
Volume186
Issue number1-2
DOIs
StatePublished - 1 May 2007

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Narcotic Antagonists
Chemokines
Tumor Necrosis Factor-alpha
Fentanyl
Opioid Analgesics
mu Opioid Receptor
Astrocytes
Morphine
Naltrexone
Transcription Factors
Cytokines

Keywords

  • Astrocyte
  • Brain injury
  • Mu-opioid receptor
  • Neuroinflammation
  • Tumor necrosis factor α

Cite this

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title = "The opioid antagonist, β-funaltrexamine, inhibits chemokine expression in human astroglial cells",
abstract = "Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)α induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-κB], we determined that NF-κB activation is instrumental in TNFα-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFα stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFα-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor β-funaltrexamine (β-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFα-induced CXCL10 expression. Rather, β-FNA dose-dependently inhibited TNFα-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and β-FNA each reduced TNFα-induced nuclear translocation of NF-κB p65. These data show that β-FNA and fentanyl inhibit TNFα-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFα-induced CXCL10 expression by fentanyl and β-FNA is not directly related to a reduction in NF-κB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, β-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.",
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The opioid antagonist, β-funaltrexamine, inhibits chemokine expression in human astroglial cells. / Davis, Randall; Buck, Daniel J.; Saffarian, Neda; Stevens, Craig.

In: Journal of Neuroimmunology, Vol. 186, No. 1-2, 01.05.2007, p. 141-149.

Research output: Contribution to journalArticle

TY - JOUR

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