Prenatal Oxycodone Exposure Alters CNS Endothelin Receptor Expression in Neonatal Rats

M. Devarapalli; M. Leonard; S. Briyal; G. Stefanov; B. L. Puppala; L. Schweig; A. Gulati

doi:10.1055/s-0035-1569279

Drug Research, Table of Contents

Drug Res (Stuttg) 2016; 66(05): 246-250
DOI: 10.1055/s-0035-1569279

Original Article

Prenatal Oxycodone Exposure Alters CNS Endothelin Receptor Expression in Neonatal Rats

M. Devarapalli

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

,

M. Leonard

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

,

S. Briyal

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

,

G. Stefanov

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

,

B. L. Puppala

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

,

L. Schweig

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

,

A. Gulati

¹Department of Pediatrics, Divisions of Neonatology and Research, Advocate Children’s Hospital and Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, USA

› Author Affiliations

Abstract

Prenatal opioid exposure such as oxycodone is linked to significant adverse effects on the developing brain. Endothelin (ET) and its receptors are involved in normal development of the central nervous system. Opioid tolerance and withdrawal are mediated through ET receptors. It is possible that adverse effect of oxycodone on the developing brain is mediated through ET receptors. We evaluated brain ET_A and ET_B receptor expression during postnatal development in rats with prenatal oxycodone exposure. Timed pregnant Sprague-Dawley rats received either oxycodone or placebo throughout gestation. After birth, male rat pups were sacrificed on postnatal day (PND) 1, 7, 14 or 28. Brain ET_A and ET_B receptor expression was determined by Western blot analysis. Oxycodone pups compared to placebo demonstrated congenital malformations of the face, mouth, and vertebrae at the time of birth [4/69 (5.7%) vs. 0/60 (0%); respectively] and intrauterine growth retardation [10/69 (15%) vs. 2/60 (3.3%); respectively]. On PND 28, oxycodone pups compared to placebo had lower body and kidney weight. ET_A receptor expression in the oxycodone group was significantly higher compared to placebo on PND 1 (p=0.035), but was similar on PND 7, 14, or 28. ET_B receptor expression decreased in oxycodone compared to placebo on PND 1 and 7 (p=0.001); and increased on PND 28 (p=0.002), but was similar on PND 14. Oxycodone-exposed rat pups had lower birth weight and postnatal weight gain and greater congenital malformations. ET_B receptor expression is altered in the brain of oxycodone-treated rat pups indicating a possible delay in CNS development.

Key words

opioid - endothelin - CNS - postnatal development - ET_A receptors - ET_B receptors

Full Text

References

References
1 Manchikanti L, Helm 2nd S, Fellows B et al. Opioid epidemic in the United States. Pain physician 2012; 15: ES9-ES38
2 Centers for Disease Control and Prevention. CDC Congressional Testimony 2007;
3 Hayes MJ, Brown MS. Epidemic of prescription opiate abuse and neonatal abstinence. Jama 2012; 307: 1974-1975
4 Logan BA, Brown MS, Hayes MJ. Neonatal abstinence syndrome: treatment and pediatric outcomes. Clinical obstetrics and gynecology 2013; 56: 186-192
5 Patrick SW, Schumacher RE, Benneyworth BD et al. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. Jama 2012; 307: 1934-1940
6 Hudak ML, Tan RC. Committee On D, Committee On F, Newborn, American Academy of P. Neonatal drug withdrawal. Pediatrics 2012; 129: e540-e560
7 Napolitano A, Theophilopoulos D, Seng SK et al. Pharmacologic management of neonatal abstinence syndrome in a community hospital. Clinical obstetrics and gynecology 2013; 56: 193-201
8 Farid WO, Dunlop SA, Tait RJ et al. The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data. Current neuropharmacology 2008; 6: 125-150
9 Liu A, Bjorkman T, Stewart C et al. Pharmacological treatment of neonatal opiate withdrawal: between the devil and the deep blue sea. International journal of pediatrics 2011; 2011: 935631
10 Kokki M, Franco MG, Raatikainen K et al. Intravenous oxycodone for pain relief in the first stage of labour–maternal pharmacokinetics and neonatal exposure. Basic & clinical pharmacology & toxicology 2012; 111: 182-188
11 Bengtsson J, Ederoth P, Ley D et al. The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep. British journal of pharmacology 2009; 157: 1085-1096
12 Maurray MHG. Labor and Delivery Nursing: Guide to Evidence-Based Practice. Springer Publishing Company; New York, NY: 2009
13 Sadiq MW, Borgs A, Okura T et al. Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. Journal of pharmaceutical sciences 2011; 100: 3912-3923
14 Lam J, Kelly L, Ciszkowski C et al. Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia. The Journal of pediatrics 2012; 160: 33 e2-37 e2
15 Poyhia R, Seppala T. Liposolubility and protein binding of oxycodone in vitro. Pharmacology & toxicology 1994; 74: 23-27
16 Gulati A, Rebello S, Chari G et al. Ontogeny of endothelin and its receptors in rat brain. Life sciences 1992; 51: 1715-1724
17 Leonard MG, Prazad P, Puppala B et al. Selective Endothelin-B Receptor Stimulation Increases Vascular Endothelial Growth Factor in the Rat Brain during Postnatal Development. Drug research 2015; 65: 607-613
18 Puppala B, Awan I, Briyal S et al. Ontogeny of endothelin receptors in the brain, heart, and kidneys of neonatal rats. Brain & development 2015; 37: 206-215
19 Bhalla S, Ali I, Lee H et al. Potentiation of oxycodone antinociception in mice by agmatine and BMS182874 via an imidazoline I2 receptor-mediated mechanism. Pharmacology, biochemistry, and behavior 2013; 103: 550-560
20 Bhalla S, Andurkar SV, Gulati A. Involvement of alpha(2)-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice. Fundamental & clinical pharmacology 2013; 27: 498-509
21 Bhalla S, Rapolaviciute V, Gulati A. Determination of alpha(2)-adrenoceptor and imidazoline receptor involvement in augmentation of morphine and oxycodone analgesia by agmatine and BMS182874. European journal of pharmacology 2011; 651: 109-121
22 Bhalla S, Zhang Z, Patterson N et al. Effect of endothelin-A receptor antagonist on mu, delta and kappa opioid receptor-mediated antinociception in mice. European journal of pharmacology 2010; 635: 62-71
23 Davis CP, Franklin LM, Johnson GS et al. Prenatal oxycodone exposure impairs spatial learning and/or memory in rats. Behavioural brain research 2010; 212: 27-34
24 Lowry OH, Rosebrough NJ, Farr AL et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275
25 Briyal S, Lavhale MS, Gulati A. Repeated administration of centhaquin to pregnant rats did not affect postnatal development and expression of endothelin receptors in the brain, heart or kidney of pups. Arzneimittel-Forschung 2012; 62: 670-676
26 Merlet-Benichou C, Gilbert T, Muffat-Joly M et al. Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatric nephrology 1994; 8: 175-180
27 Barni T, Fantoni G, Gloria L et al. Role of endothelin in the human craniofacial morphogenesis. Journal of craniofacial genetics and developmental biology 1998; 18: 183-194
28 Van Woerkom R, Beharry KD, Modanlou HD et al. Influence of morphine and naloxone on endothelin and its receptors in newborn piglet brain vascular endothelial cells: clinical implications in neonatal care. Pediatric research 2004; 55: 147-151
29 Siren AL, Lewczuk P, Hasselblatt M et al. Endothelin B receptor deficiency augments neuronal damage upon exposure to hypoxia-ischemia in vivo. Brain research 2002; 945: 144-149
30 Vidovic M, Chen MM, Lu QY et al. Deficiency in endothelin receptor B reduces proliferation of neuronal progenitors and increases apoptosis in postnatal rat cerebellum. Cellular and molecular neurobiology 2008; 28: 1129-1138
31 Arguello AA, Fischer SJ, Schonborn JR et al. Effect of chronic morphine on the dentate gyrus neurogenic microenvironment. Neuroscience 2009; 159: 1003-1010
32 Leonard MG, Gulati A. Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats. Brain research 2013; 1528: 28-41