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

Journal of Perinatology volume 33, pages 374–382 (2013)Cite this article

Subjects

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 <10–9 M increased IL-6, while 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 >10–5M 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.

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Acknowledgements

The authors gratefully acknowledge Dr Frances Northington and Dr Robert Bennett for their support; Mrs Debra Flock and Ms Ariel Mason for their administrative assistance and the obstetric team at Johns Hopkins Hospital for their kind support with patient enrollment. We are also indebted to our patients and their families for their willingness to participate in this study. This study was financially supported by the National Institute for Drug Abuse (NIDA) R25DA021630 (EBG).

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Authors and Affiliations

  1. Department of Pediatrics, Division of Neonatology, Johns Hopkins University—School of Medicine, Baltimore, MD, USA

    R Chavez-Valdez, L Kovell, R Ahlawat, G L McLemore & E B Gauda

  2. Department of Pediatrics, Division of Neonatology, Texas Tech University—Health Sciences Center, Odessa, TX, USA

    R Chavez-Valdez

  3. Department of Biology, Morgan State University, Baltimore, MD, USA

    G L McLemore

  4. Division of Immunobiology, Children’s Hospital of Cincinnati, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    M Wills-Karp

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  1. R Chavez-Valdez
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Correspondence to R Chavez-Valdez.

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Chavez-Valdez, R., Kovell, L., Ahlawat, R. et al. Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells. J Perinatol 33, 374–382 (2013). https://doi.org/10.1038/jp.2012.124

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