The present study was designed to investigate the effects of prenatal morphine exposure on the hypothalamic-pituitary-adrenal (HPA) axis-regulated stress responses by measuring restraint stress-induced changes in the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels. In experiment 1, plasma levels of ACTH and CORT in prenatally morphine-, saline-exposed and control male rats were determined before and at several times after restraint stress. There were no statistically significant differences in plasma ACTH and CORT levels before restraint stress between the groups. However, prenatal morphine exposure dampened the stress-induced increase and spontaneous recovery of ACTH levels after the restraint stress. There were no differences in plasma CORT levels between the three groups either before or at any time after restraint stress. Experiment 2 was designed to investigate the sensitivity of negative feedback of glucocorticoids using the dexamethasone (DEX) suppression test. DEX was administered at different doses (0.001, 0.01, 0.1 and 1.0 mg/kg) and ACTH and CORT plasma levels were measured before and at several times after restraint stress in prenatally morphine- and saline-exposed males. DEX pretreatment eliminated the differences observed in ACTH responses to stress in morphine- and saline-exposed males. DEX pretreatment dose dependently suppressed the restraint stress-induced increased plasma ACTH concentration. In plasma CORT levels, DEX pretreatment dose dependently suppressed the restraint stress-induced increased plasma CORT concentration regardless of prenatal drug exposure. Thus, the present study demonstrates that prenatal morphine exposure alters the ACTH and CORT responses to stress but not the sensitivity of negative feedback of glucocorticoids.

Keywords:
Opioid peptides, Corticotropin, Adrenal steroids, Stress, Neonatal imprinting
1.
Adamson WT, Windh RT, Blackford S, Kuhn CM: Ontogeny of μ- and κ-opiate receptor control of the hypothalamo-pituitary-adrenal axis in rats. Endocrinology 1991;129:959–964.
2.
Albeck DS, McKittrick CR, Blanchard DC, Blanchard RJ, Nikulina J, McEwen BS, Sakai RR: Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain. J Neurosci 1997;17:4895–4903.
3.
Brain P, Benton D: The interpretation of physiological correlates of differential housing in laboratory rats. Life Sci 1979;24:99–115.
4.
Buckingham JC, Cooper TA: Differences in hypothalamo-pituitary-adrenocortical activity in the rat after acute and prolonged treatment with morphine. Neuroendocrinology 1984;38:411–417.
5.
Buckingham JC, Cooper TA: Interrelationships of opioidergic and adrenergic mechanisms controlling the secretion of corticotrophin releasing factor in the rat. Neuroendocrinology 1987;46:199–206.
6.
Dallman MF, Akana SF, Jacobson L, Levin N, Cascio CS, Shinsako J: Characterization of corticosterone feedback regulation of ACTH secretion. Ann NY Acad Sci 1987;512:402–414.
7.
Dutriez-Casteloot I, Bernet F, Dedieu JF, Croix D, Laborie C, Montel V, Lesage J, Beauvillain JC, Dupouy JP: Hypothalamic-pituitary-adrenocortical and gonadal axes and sympathoadrenal activity of adult male rats prenatally exposed to morphine. Neurosci Lett 1999;263:1–4.
8.
Eisenberg RM: Effects of chronic treatment with diazepam, phenobarbital, or amphetamine on naloxone-precipitated morphine withdrawal. Drug Alcohol Depend 1985;15:375–381.
9.
Fukunaga Y, Nishida S, Inoue N, Miyamoto M, Kishioka S, Yamamoto H: Time course of morphine withdrawal and preproenkephalin gene expression in the periaqueductal gray of rats. Brain Res Mol Brain Res 1998;55:221–231.
10.
Giralt M, Armario A: Individual housing does not influence the adaptation of the pituitary-adrenal axis and other physiological variables to chronic stress in adult male rats. Physiol Behav 1989;45:477–481.
11.
Guaza C, Torrellas A, Borrell J, Borrell S: Effects of morphine upon the pituitary-adrenal system and adrenal catecholamines: A comparative study in cats and rats. Pharmacol Biochem Behav 1979;11:57–63.
12.
Handa RJ, Burgess LH, Kerr JE, O’Keefe JA: Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. Horm Behav 1994;28:464–476.
13.
Hatch AM, Wiberg GS, Zawidzka Z, Cann M, Airth JM, Grice HC: Isolation syndrome in the rat. Toxicol Appl Pharmacol 1965;7:737–745.
14.
Houshyar H, Cooper ZD, Woods JH: Paradoxical effects of chronic morphine treatment on the temperature and pituitary-adrenal responses to acute restraint stress: A chronic stress paradigm. J Neuroendocrinol 2001;13:862–874.
15.
Houshyar H, Galigniana MD, Pratt WB, Woods JH: Differential responsivity of the hypothalamic-pituitary-adrenal axis to glucocorticoid-negative feedback and corticotropin releasing hormone in rats undergoing morphine withdrawal: Possible mechanisms involved in facilitated and attenuated stress responses. J Neuroendocrinol 2001;13:875–886.
16.
Choi SJ, Mazzio EA, Reams RR, Soliman KF: Gestational cocaine exposure alters postnatal pituitary-adrenal axis activity and stress endurance in rats. Ann NY Acad Sci 1998;844:336–345.
17.
Ignar DM, Kuhn CM: Effects of specific μ and κ opiate tolerance and abstinence on hypothalamo-pituitary-adrenal axis secretion in the rat. J Pharmacol Exp Ther 1990;255:1287–1295.
18.
Ježová D, Vigas M, Jurčovičová J: ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone-treated rats. Life Sci 1982;31:307–314.
19.
Leonard BE: Stress, norepinephrine and depression. J Psychiatry Neurosci 2001;26:S11–S16.
20.
Lesage J, Bernet F, Montel V, Dupouy JP: Effects of prenatal morphine on hypothalamic metabolism of neurotransmitters and gonadal and adrenal activities, during the early postnatal period in the rat. Neurochem Res 1996;21:723–732.
21.
Lesage J, Bernet F, Montel V, Dutriez-Casteloot I, Dupouy JP: Influence of morphine treatment in pregnant rats on the mineralocorticoid activity of the adrenals in their neonates. Life Sci 2000;66:1197–1211.
22.
Lesage J, Grino M, Bernet F, Dutriez-Casteloot I, Montel V, Dupouy JP: Consequences of prenatal morphine exposure on the hypothalamo-pituitary-adrenal axis in the newborn rat: Effect of maternal adrenalectomy. J Neuroendocrinol 1998;10:331–342.
23.
Lotti VJ, Kokka N, George R: Pituitary-adrenal activation following intrahypothalamic microinjection of morphine. Neuroendocrinology 1969;4:326–332.
24.
McCormick CM, Smythe JW, Sharma S, Meaney MJ: Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats. Brain Res Dev Brain Res 1995;84:55–61.
25.
Meaney MJ, Aitken DH, Bhatnagar S, Sapolsky RM: Postnatal handling attenuates certain neuroendocrine, anatomical and cognitive dysfunctions associated with aging in female rats. Neurobiol Aging 1991;12:31–38.
26.
Meaney MJ, Aitken DH, Bodnoff SR, Iny LJ, Tatarewicz JE, Sapolsky RM: Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions. Behav Neurosci 1985;99:765–770.
27.
Meaney MJ, Aitken DH, Sharma S, Viau V: Basal ACTH, corticosterone and corticosterone-binding globulin levels over the diurnal cycle, and age-related changes in hippocampal type I and type II corticosteroid receptor binding capacity in young and aged, handled and nonhandled rats. Neuroendocrinology 1992;55:204–213.
28.
Meaney MJ, Aitken DH, Viau V, Sharma S, Sarrieau A: Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat. Neuroendocrinology 1989;50:597–604.
29.
Meaney MJ, Bhatnagar S, Larocque S, McCormick C, Shanks N, Sharma S, Smythe J, Viau V, Plotsky PM: Individual differences in the hypothalamic-pituitary-adrenal stress response and the hypothalamic CRF system. Ann NY Acad Sci 1993;697:70–85.
30.
Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM: Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress. Dev Neurosci 1996;18:49–72.
31.
Milanes MV, Puig MM, Vargas ML: Simultaneous changes in hypothalamic catecholamine levels and plasma corticosterone concentration in the rat after acute morphine and during tolerance. Neuropeptides 1993;24:279–284.
32.
Nelson LR, Taylor AN, Lewis JW, Poland RE, Redei E, Branch BJ: Pituitary-adrenal responses to morphine and footshock stress are enhanced following prenatal alcohol exposure. Alcohol Clin Exp Res 1986;10:397–402.
33.
Pacák K: Stressor-specific activation of the hypothalamic-pituitary-adrenocortical axis. Physiol Res 2000;49:S11–S17.
34.
Peters DA: Prenatal stress: Effects on brain biogenic amine and plasma corticosterone levels. Pharmacol Biochem Behav 1982;17:721–725.
35.
Peters DA: Prenatal stress increases the behavioral response to serotonin agonists and alters open field behavior in the rat. Pharmacol Biochem Behav 1986;25:873–877.
36.
Šlamberová R, Schindler CJ, Vathy I: Impact of maternal morphine and saline injections on behavioral responses to cold water stressor in adult male and female progeny. Physiol Behav 2002;75:723–732.
37.
Spear LP: Assessment of the effects of developmental toxicants: Pharmacological and stress vulnerability of offspring. NIDA Res Monogr 1996;164:125–145.
38.
Stefanski V: Social stress in laboratory rats: Hormonal responses and immune cell distribution. Psychoneuroendocrinology 2000;25:389–406.
39.
Takahashi LK, Turner JG, Kalin NH: Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats. Brain Res 1992;574:131–137.
40.
Tallarida RJ, Murray RB: Manual of Pharmacologic Calculations with Computer Programs, ed 2. New York, Springer, 1987.
41.
Taylor AN, Branch BJ, Liu SH, Kokka N: Long-term effects of fetal ethanol exposure on pituitary-adrenal response to stress. Pharmacol Biochem Behav 1982;16:585–589.
42.
Vallee M, Mayo W, Maccari S, Le Moal M, Simon H: Long-term effects of prenatal stress and handling on metabolic parameters: Relationship to corticosterone secretion response. Brain Res 1996;712:287–292.
43.
Vanitallie TB: Stress: A risk factor for serious illness. Metabolism 2002;51:40–45.
44.
Vathy I: Maternal opiate exposure: Long-term CNS consequences in the stress system of the offspring. Psychoneuroendocrinology 2002;27:273–283.
45.
Vathy I, Etgen AM, Barfield RJ: Effects of prenatal exposure to morphine on the development of sexual behavior in rats. Pharmacol Biochem Behav 1985;22:227–232.
46.
Vathy I, He HJ, Iodice M, Hnatczuk OC, Rimanóczy Á: Prenatal morphine exposure differentially alters TH-immunoreactivity in the stress-sensitive brain circuitry of adult male and female rats. Brain Res Bull 2000;51:267–273.
47.
Vathy I, Rimanóczy Á, Eaton RC, Kátay L: Modulation of catecholamine turnover rate in brain regions of rats exposed prenatally to morphine. Brain Res 1994;662:209–215.
48.
Vathy IU, Etgen AM, Rabii J, Barfield RJ: Effects of prenatal exposure to morphine sulfate on reproductive function of female rats. Pharmacol Biochem Behav 1983;19:777–780.
49.
Weinberg J: Hyperresponsiveness to stress: Differential effects of prenatal ethanol on males and females. Alcohol Clin Exp Res 1988;12:647–652.
50.
Weinberg J, Gallo PV: Prenatal ethanol exposure: Pituitary-adrenal activity in pregnant dams and offspring. Neurobehav Toxicol Teratol 1982;4:515–520.
51.
Weinstock M: Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 2001;65:427–451.
52.
Wotus C, Levay-Young BK, Rogers LM, Gomez-Sanchez CE, Engeland WC: Development of adrenal zonation in fetal rats defined by expression of aldosterone synthase and 11β-hydroxylase. Endocrinology 1998;139:4397–4403.
© 2003 S. Karger AG, Basel
2003
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.