Review Opioid Modulation of Oxytocin Release Mark S. Morris, BA, Edward F. Domino, MD, and Steven E. Domino, MD Analgesia or anesthesia is frequently used for women in of a labor without sufficient cervical dilatation. This labor. A wide range of opioid analgesics with vastly differ- review discusses the scientific basis for opioid modulation ent pharmacokinetics, potencies, and potential side effects of oxytocin release from the posterior pituitary and the can be considered by physicians and midwives for labor- practical implications of this relationship to explain well- ing patients requesting pain relief other than a labor epi- known clinical observations of the effect of morphine on dural. The past 50 years have seen the use of the classic prodromal labor. mu opioid agonist morphine and other opioids diminish markedly for several reasons, including availability of Keywords: endogenous opioids; morphine; meperidine; epidural anesthetics, side effects, formulary restrictions, mu-kappa-delta opioid receptors; oxytocin; and concern for neonatal respiratory depression. Morphine parturition; vasopressin is now primarily used in obstetrics to provide rest and Journal of Clinical Pharmacology, 2010;50:1112-1117 sedation as appropriate for the stressed prodromal stages © 2010 The Author(s) he major hormone involved with parturition to system in modulating oxytocin release, it is of inter- Tstimulate uterine contractions is oxytocin. est to note the use of exogenous mu opioids such as Russell et al1 have reviewed the extensive literature morphine and meperidine in human parturition. on the complexity of the magnocellular oxytocin Different forms of analgesia/anesthesia are needed system. Endogenous opioids mechanisms inhibit for both the benefit of the woman in labor and her oxytocin release as part of the multiple hormones baby. In the United States today, about 1 in 3 women involved, including relaxin, estrogen, progesterone, and their caretakers are opting for cesarean sections, and autoinhibition by nitric oxide. typically as elective, scheduled surgery.2 The Cochrane Oxytocin is produced in the hypothalamus and is protocol for the use of parenteral opioids for mater- released into systemic circulation via the posterior nal pain relief in labor is especially useful.3 The lobe of the pituitary gland. Specifically, oxytocin is availability of a wide range of analgesics with vastly made in magnocellular neurosecretory cells of the different pharmacology, pharmacokinetics, milli- supraoptic nucleus and paraventricular nucleus of gram potencies, routes of administration, and side the hypothalamus. It is well established that oxy- effects is impressive. Nevertheless, morphine use tocin is involved in a positive feedback loop during during labor has had a checkered pro and con his- parturition, in which oxytocin causes uterine con- tory over the years. During its use to produce twi- tractions, which in turn lead to more oxytocin light sleep, it became clear that although analgesia release. This feed-forward loop continues until par- and amnesia for the mother was desirable, some turition. Oxytocin is also released when an infant women became excited and delirious. In addition, suckles at the nipple of a lactating mother and acts newborns frequently showed apnea. Thus, twilight at the mammary glands, causing milk letdown. In sleep was abandoned years ago. Its replacement view of the importance of the endogenous opioids with meperidine alone or in combination with pro- methazine also had a pro and con history of increased use to abandonment. Meperidine has a complex From the Departments of Pharmacology (Mr Morris, Dr E. F. Domino); pharmacology in addition to having mu opioid anal- and Obstetrics and Gynecology (Dr S. E. Domino), University of gesic properties. DeVoe et al4 reported that meperid- Michigan, Ann Arbor. Submitted for publication November 19, ine alone or in combination with promethazine, 2009; revised version accepted December 20, 2009. Address correspondence to S. E. Domino, MD, Department of Obstetrics and although analgesic, did not decrease but actually Gynecology, University of Michigan, Ann Arbor, MI 48109-5617; increased uterine activity over control from about 7 e-mail: [email protected]. to 20-30 Torr/min units of uterine activity over 10 to DOI:10.1177/0091270010361256 30 minutes. Many other opioids have been used 1112 •• JJ Clin Clin Pharmacol Pharmacol xxxx;xx:x-x 2010;50:1112-1117 OPIOID MODULATION OF OXYTOCIN RELEASE since, again with mixed results. Today, morphine is other published animal and human pituitary data used in a subset of obstetrical patients to provide that indicated negligible delta opioid binding. rest and sedation as appropriate for the stressed pro- Naltrindole has been found to bind to mu and kappa dromal stages of a labor without sufficient cervical in addition to delta receptors,11 which could account dilation with a fetus in no stress. This review pro- for the different conclusions. vides a rational scientific basis to its current use and shows why it is useful for more than just rest and Mu OPiOid MOdulaTiOn Of POsTeRiOR sedation for patients. PiTuiTaRy hORMOne Release OPiOid ReCePTORs in The PiTuiTaRy Opioid binding in the posterior pituitary is impor- tant because of the effect on oxytocin and vaso- Controversy exists over the nature of opiate binding in pressin release. Both mu and kappa opioid receptor the posterior pituitary.11 C-carfentanil (a selective mu agonists have been shown to affect posterior pitui- opioid receptor agonist) is known to have relatively tary hormone release. Oxytocin secretion is inhib- high binding potential in the human pituitary similar ited centrally by both mu and kappa agonists or to classical opiate binding areas in the brain, but its directly at the posterior pituitary via kappa recep- clinical significance remains unknown.5,6 However, tors. Lutz-Bucher and Koch12 isolated the rat neu- positron emission tomography (PET) imaging does not rointermediate as well as the neural lobe (posterior distinguish whether binding is in the anterior or pituitary). Removal of the endogenous opiate-rich posterior lobes. Relatively large doses of naloxone (1 mg/ pars intermedia cells from the pars nervosa enhanced kg) do not completely displace 11C-carfentanil binding both oxytocin and vasopressin release. Morphine in the pituitary compared to other brain areas, indicat- inhibited their release from both lobes, but the neu- ing the presence of a nonopioid binding site.5,6 One rointermediate lobe needed a larger concentration. possibility is that a metabolite of 11C-carfentanil such Naloxone reversed the effects of morphine, indicat- as 11C-methanol may be involved. ing a primarily mu opioid receptor action. Simantov and Snyder7 reported the presence Clarke and Patrick13 studied isolated rat pars ner- of mu opiate binding in bovine intermediate and vosa with attached pars intermedia. They electri- posterior but very little in the anterior pituitary, cally stimulated the pituitary stalk to measure where beta-endorphin is released.8 Jordan et al9 oxytocin and vasopressin release. Morphine inhib- studied postmortem pituitaries from 5 human par- ited both oxytocin and vasopressin release. Naloxone ticipants without neuroendocrine or neuronal dis- reversed morphine inhibition of oxytocin but not ease. They used (125I)-FK-33-824 for mu, (125I)[D.Ala2] vasopressin release. Bicknell et al14 found that oxy- Deltorphin-I for delta, and 3H-U69,593 for kappa tocin cells develop dependence with added mor- opioid sites. Quantitative in vitro autoradiography phine and eventually require morphine to function of pituitary sections with each radioactive ligand normally. When naloxone was given, the firing rate indicated the absence of significant labeling in the of oxytocin-secreting cells increased 360% and anterior lobe but high binding in the posterior pitui- plasma oxytocin levels increased 100 times greater tary. All 5 posterior pituitary specimens had signifi- than in controls. No significant difference was cant mu and kappa binding sites that almost overlap observed in vasopressin levels. Zhao et al15 also completely but had no significant delta binding found in rats that naloxone increased oxytocin sites. These investigators further showed that both release 100% and 173% in 2 experiments and vaso- the mu and kappa opioid binding was competitively pressin release only 30% and 20%, respectively. antagonized by other selective opioid ligands. The Pumford et al16 showed that morphine depresses more recent PET study by Weerts et al10 also demon- the firing rate of supraoptic oxytocin neurons when strated a specific mu opioid binding site in the given intracerebroventricularly (ICV) and intrave- human pituitary. These investigators studied mu as nously (IV). Both morphine tolerance and depend- well as delta opioid brain and pituitary binding in ence developed in magnocellular oxytocin neurons recently abstinent alcohol-dependent participants during 5 days of ICV infusion. The researchers sug- treated with naltrexone. The naltrexone-treated subjects gested that tolerance and dependence to endogenous had decreased binding in the pituitary for both opioids is important for oxytocin neurons during 11C-carfentanil (mu) and 11C-naltridole (delta). Delta pregnancy, in preparation for parturition. opioid binding in the human brain and pituitary was Ortiz-Miranda et al17,18 reported that mu opioid present but minimal. This latter finding differs from receptors modulate rat neurohypophyseal