Warning message

This content is filtered. APPPAH membership is required for full access to journal articles.
-A +A
Publication Date: 
May, 1991
Page Count: 
Starting Page: 

The perinatal opioid syndrome has been recognized for over a century. Examination of this phenomena has revealed no pathognomonic symptoms, but rather a constellation of somatic and neurobiological deficits that may continue into adulthood. Research in this area has found that exogenous opioids such as heroin and methadone interact with opioid receptors and influence development. Moreover, a fundamental and important observation shows that endogenous opioid peptides, the counterpart to exogenous opioids, normally modulate developmental events. Opioids are inhibitory growth factors that tonically mediate their action by way of the opioid receptor. Studies now reveal that [Met5]-enkephalin, a naturally occurring neuropeptide derived from proenkephalin A, is the most potent opioid peptide in regulating growth and acts on a newly discovered opioid receptor-the zeta (f) receptor. Cell proliferation appears to be the major target of growth-related opioids. Exogenous opioids such as methadone and heroin also have an affinity for the zeta receptor, and involvement of these compounds with growth can be envisioned. Continued study of endogenous opioid systems and developmental processes, particularly at the cell and molecular level, may permit elucidation of the etiology and pathogenesis of various abnormalities (e.g., mental retardation, tumorigenesis) associated with neural development.


1. Blum RH, A history of opium. In: Blum RH and Associates, eds. Society and Drugs. I. Social and cultural observations. San Francisco: Jossey-Bass, 1969:45-58.

2. Zagon IS, McLaughlin PJ, Weaver DJ, Zagon E. Opiates, endorphins, and the developing organism: a comprehensive bibliography. Neurosci Biobehav Rev 1982; 6:439-479.

3. Zagon IS, McLaughlin PJ. Endogenous opioid systems and neurobehavioral development. In: Rodgers RJ, Cooper SJ, eds. Endorphins, Opiates and Behavioral Processes. Chichester: John Wiley and Sons, 1988:287-309.

4. Zagon IS, McLaughlin PJ. An overview of the neurobehavioral sequelae of perinatal opioid exposure. In: Yanai J, ed. Neurobehavioral Teratology. Amsterdam: Elsevier, 1984:197-234.

5. Pert CB, Snyder SH. Opiate receptor: a demonstration in nervous tissue. Science 1973; 179:1011-1014.

6. Terenius L. Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol Toxicol 1973; 32:317-320.

7. Simon EJ, Miller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic PH]etorphine to rat brain homogenate. Proc Natl Acad Sci 1973; 70:1947-1949.

8. Hughes JA, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of the pentapeptides from the brain with potent opiate agonist activity. Nature 1975; 258:577-579.

9. Smith AA, Hui FW, Crofford MJ. Inhibition growth in young mice treated with d,lmethadone. European J Pharmacol 1977; 43:307-314.

10. McLaughlin PJ, Zagon IS. Opioid regulation of neurotumor cell growth in vitro. Soc Neurosci Abst 1984; 10:1111.

11. Zagon, IS, McLaughlin PJ. Increased brain size and cellular content in infant rats treated with an opiate antagonist. Science 1983; 221: 1179-1180.

12. Zagon IS, McLaughlin PJ. Naltrexone modulates growth in infant rats. Life Sci 1983; 33:2449-2454.

13. Zagon IS, McLaughlin PJ. Naltrexone modulates body and brain development in rats: a role for endogenous opioids in growth. Life Sci 1984; 35:2057-2064.

14. Zagon IS, McLaughlin PJ. Naltrexone's influence on neurobehavioral development. Pharmacol Biochem Behav 1985; 22:441-448.

15. Zagon IS, McLaughlin PJ. Opioid antagonist-induced regulation of organ development. Physiol Behav 1985; 34:507-511.

16. Zagon IS, McLaughlin PJ. Opioid antagonist (naltrexone) modulation of cerebellar development: histological and morphometric studies. J Neurosci 1986; 6:1424-1432.

17. Zagon IS, McLaughlin PJ. Opioid antagonist-induced modulation of cerebral and hippocampal development: histological and morphometric studies. Devel Brain Res 1986; 28:233-246.

18. Zagon IS, McLaughlin PJ. Endogenous opioid systems regulate cell proliferation in the developing rat brain. Brain Res 1987; 412:68-72.

19. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioids regulate dendritic growth and spine formation in developing rat brain. Brain Res 1987; 416:157-161.

20. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioid systems and the regulation of dendritic growth and spine formation. J Comp Neurol 1989; 281:13-22.

21. Zagon IS, McLaughlin PJ. Naloxone modulates body and organ growth of rats: dependency on the duration of opioid receptor blockade and stereospecificity. Pharmacol Biochem Behav 1989; in press.

22. Tang AH, Collins RJ. Enhanced analgesic effect of morphine after chronic administration of naloxone in the rat. European J Pharmacol 1979; 47:473-474.

23. Bardo MT, Bhatnagar RB, Gebhart GF. Differential effects of chronic morphine and naloxone on opiate receptors, monoamines, and morphine-induced behaviors in preweanling rats. Devel Brain Res 1982; 4:139-147.

24. Zagon IS, McLaughlin PJ. Opioid antagonist modulation of murine neuroblastoma: a profile of cell proliferation and opioid peptides and receptors. Brain Res 1989; 480:16-28.

25. Zagon IS, Rhodes RE, McLaughlin PJ. Localization of enkephalin immunoreactivity in germinative cells of the developing rat cerebellum. Science 1985; 227:1049-1051.

26. Zagon IS, McLaughlin PJ. Endogenous opioid systems regulate growth of neural tumor cells in culture. Brain Res 1989; 490:14-25.

27. Zagon IS, Goodman SR, McLaughlin PJ. Characterization of zeta (?): a new opioid receptor involved in growth. Brain Res 1989; 482:297-305.

Ian S. Zagon, Ph.D. and Patricia J. McLaughlin, Ph.D.

Ian S. Zagon and Patricia J. McLaughlin are with the Department of Anatomy, Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033. Address correspondence to Professor Zagon. This review was prepared under NIH grants NS-20500 and NS-20623.