Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells

Raul Chavez-Valdez, L. Kovell, R. Ahlawat, G. L. McLemore, Marsha Wills-Karp, Estelle B Gauda

Research output: Contribution to journalArticle

Abstract

Objective:Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.Study Design:Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term (≥37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM.Result:Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10 -5 M decreased all tested cytokines except IL-8. In contrast, clonidine at 10 -5 M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10 -5 M decreased the expression of μ-OPR, but not δ- or κ-OPRs.Conclusion:Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.

Original languageEnglish (US)
Pages (from-to)374-382
Number of pages9
JournalJournal of perinatology : official journal of the California Perinatal Association
Volume33
Issue number5
DOIs
StatePublished - Apr 2013

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Cytokine Receptors
Clonidine
Opioid Receptors
Opioid Analgesics
Fentanyl
Methadone
Morphine
Cytokines
Interleukin-8
Interleukin-1
Cyclic AMP
Interleukin-10
Gestational Age
Newborn Infant
Premature Infants
Analgesia
Lipopolysaccharides
Interleukin-6
Down-Regulation
Gene Expression

Keywords

  • clonidine
  • fentanyl
  • inflammation
  • methadone
  • morphine
  • newborns

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Pediatrics, Perinatology, and Child Health

Cite this

@article{3817c4a0018749948af5df44e2bbe1d8,
title = "Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells",
abstract = "Objective:Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.Study Design:Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term (≥37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM.Result:Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10 -5 M decreased all tested cytokines except IL-8. In contrast, clonidine at 10 -5 M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10 -5 M decreased the expression of μ-OPR, but not δ- or κ-OPRs.Conclusion:Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.",
keywords = "clonidine, fentanyl, inflammation, methadone, morphine, newborns",
author = "Raul Chavez-Valdez and L. Kovell and R. Ahlawat and McLemore, {G. L.} and Marsha Wills-Karp and Gauda, {Estelle B}",
year = "2013",
month = "4",
doi = "10.1038/jp.2012.124",
language = "English (US)",
volume = "33",
pages = "374--382",
journal = "Journal of Perinatology",
issn = "0743-8346",
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}

TY - JOUR

T1 - Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells

AU - Chavez-Valdez, Raul

AU - Kovell, L.

AU - Ahlawat, R.

AU - McLemore, G. L.

AU - Wills-Karp, Marsha

AU - Gauda, Estelle B

PY - 2013/4

Y1 - 2013/4

N2 - Objective:Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.Study Design:Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term (≥37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM.Result:Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10 -5 M decreased all tested cytokines except IL-8. In contrast, clonidine at 10 -5 M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10 -5 M decreased the expression of μ-OPR, but not δ- or κ-OPRs.Conclusion:Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.

AB - Objective:Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.Study Design:Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term (≥37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM.Result:Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10 -5 M decreased all tested cytokines except IL-8. In contrast, clonidine at 10 -5 M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10 -5 M decreased the expression of μ-OPR, but not δ- or κ-OPRs.Conclusion:Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.

KW - clonidine

KW - fentanyl

KW - inflammation

KW - methadone

KW - morphine

KW - newborns

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