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 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, 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. Results Following LPS 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 >10-5M decreased all tested cytokines except IL-8. In contrast, clonidine at <10-9M increased IL-6, while at >10-5M 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 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 mononuclear cells 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.

Dose-Dependent Effects of Morphine Exposure on mRNA and microRNA (miR) Expression in Hippocampus of Stressed Neonatal Mice

“…Critically ill preterm and full-term infants in the neonatal intensive care unit (NICU) undergo inescapable stress, often for prolonged periods. These infants are commonly exposed to high doses of morphine to provide analgesia, sedation, and to treat neonatal abstinence syndrome [ 1 ]. The individual and combined effects of stress and morphine may affect neurodevelopment [ 2 ].…”

Maternal opioid use is reflected on leukocyte telomere length of male newborns

“…In this regard, to the best of our knowledge there is only two reports, one assessing in vitro effect of opioid treatment on cultured whole cord blood cells of neonates, which observed a suppression of most of cytokines [ 54 ], which is more reflective of the effect of opioid administration in infants (post-natal) rather than the prenatal exposure to opioids. The other report studied rat animal model prenatally exposed to opioid and found elevated in vitro activation of peripheral blood mononuclear cells (PBMCs) and increased cytokine and chemokine production indicative of immune hyperactivity [ 55 ]. We suggest future studies that would directly assess cell count, cytokine measurement and cytogenetic damage levels in blood of human neonates born to opioid consumer mothers to provide a better answer to this question.…”

Do All Opioid Drugs Share the Same Immunomodulatory Properties? A Review From Animal and Human Studies

“…Morphine and methadone are often used for treatment of neonatal abstinence syndrome (NAS). Therefore, Chavez-Valdez et al (37) analyzed whether clinically relevant concentrations of different opioids may modify cytokine levels in cultured whole blood from preterm and full-term infants. All three MOR, KOR, DOR genes were expressed in mononuclear cells from preterm and full-term infants.…”