The opioid antagonist, beta-funaltrexamine, inhibits chemokine expression in human astroglial cells.
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)alpha induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-kappaB], we determined that NF-kappaB activation is instrumental in TNFalpha-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFalpha stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFalpha-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor beta-funaltrexamine (beta-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFalpha-induced CXCL10 expression. Rather, beta-FNA dose-dependently inhibited TNFalpha-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and beta-FNA each reduced TNFalpha-induced nuclear translocation of NF-kappaB p65. These data show that beta-FNA and fentanyl inhibit TNFalpha-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFalpha-induced CXCL10 expression by fentanyl and beta-FNA is not directly related to a reduction in NF-kappaB 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, beta-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.
Davis
Randall L
RL
Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, 1111 W. 17th Street, Tulsa, Oklahoma 74107, USA. randall.davis@okstate.edu
Buck
Daniel J
DJ
Saffarian
Neda
N
Stevens
Craig W
CW
D000704:Analysis of Variance; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001254:Astrocytoma; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D054357:Chemokine CXCL10; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005283:Fentanyl / Q000494:pharmacology; D006801:Humans; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology
D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D009292:Narcotic Antagonists; D009294:Narcotics; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; D005283:Fentanyl