Effects Of Opioid Receptor Blockade Research Articles

Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. Randomized, double-blinded, placebo-controlled crossover study. Academic research center. Healthy non-diabetic volunteers. Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Naltrexone alters cardiovascular function following acute forced swimming in mice.

PurposeNaltrexone (NTX) is an opioid antagonist that can reverse the physiological effects of opioid receptors when bound. Opioid receptors have been found to play a role in cardiovascular (CV) function, and thus, binding of NTX may alter CV activity at rest and in response to acute and chronic exercise (EX). We hypothesized that opioid receptor blockade will alter the typical CV responses following acute EX.MethodsWe assessed the effects of opioid receptor blockade on CV function via echocardiography in mice following an acute bout of forced swimming (FSw), a model of rodent EX. We administered opioid receptor antagonist, NTX, or saline in mice before FSw and in the absence of an FSw perturbation. Furthermore, we assessed how NTX can influence maximal EX capacity on a rodent treadmill.ResultsOur data shows that NTX administration does not decrease maximal EX capacity in mice (P > 0.05). However, NTX attenuated cardiac output following FSw (FSw = 52.5 ± 2.5 ml/min vs. FSw + NTX = 32.7 ± 5.2 ml/min; P < 0.05) when compared with saline control (33.5 ± 3.8 ml/min). Further, the administration of NTX in the non-EX condition significantly (P < 0.05) reduced ejection fraction.ConclusionThese data suggest that normal opioid receptor activation is necessary for typical CV function following FSw.

Opioid neurotransmission modulates defensive behavior and fear-induced antinociception in dangerous environments

The effects of endogenous opioid peptide antagonists on panic-related responses are controversial. Using elevated mazes and a prey-versus-predator paradigm, we investigated the involvement of the endogenous opioid peptide-mediated system in the modulation of anxiety- and panic attack-induced responses and innate fear-induced antinociception in the present work. Wistar rats were intraperitoneally pretreated with either physiological saline or naloxone at different doses and were subjected to either the elevated plus- or T-maze test or confronted by Crotalus durissus terrificus. The defensive behaviors of the rats were recorded in the presence of the predator and at 24h after the confrontation, when the animals were placed in the experimental enclosure without the rattlesnake. The peripheral non-specific blockade of opioid receptors had a clear anxiolytic-like effect on the rats subjected to the elevated plus-maze but not on those subjected to the elevated T-maze; however, a clear panicolytic-like effect was observed, i.e., the defensive behaviors decreased, and the prey-versus-predator interaction responses evoked by the presence of the rattlesnakes increased. A similar effect was noted when the rats were exposed to the experimental context in the absence of the venomous snake. After completing all tests, the naloxone-treated groups exhibited less anxiety/fear-induced antinociception than the control group, as measured by the tail-flick test. These findings demonstrate the anxiolytic and panicolytic-like effects of opioid receptor blockade. In addition, the fearlessness behavior displayed by preys treated with naloxone at higher doses enhanced the defensive behavioral responses of venomous snakes.

Delta-opioid receptor antagonism leads to excessive ethanol consumption in mice with enhanced activity of the endogenous opioid system

The opioid system modulates the central reinforcing effects of ethanol and participates in the etiology of addiction. However, the pharmacotherapy of ethanol dependence targeted on the opioid system is little effective and varies due to individual patients' sensitivity. In the present study, we used two mouse lines with high (HA) and low (LA) activity of the endogenous opioid system to analyze the effect of opioid receptor blockade on ethanol drinking behavior. We found that LA and HA lines characterized by divergent magnitudes of swim stress-induced analgesia also differ in ethanol intake and preference. Downregulation of the opioid system in LA mice was associated with increased ethanol consumption. Treatment with a non-selective opioid receptor antagonist (naloxone) had no effect on ethanol intake in this line. Surprisingly, in HA mice, the blockage of opioid receptors led to excessive ethanol consumption. Moreover, naloxone selectively induced high levels of anxiety- and depressive-like behaviors in HA mice which was attenuated by ethanol. With the use of specific opioid receptor antagonists we showed that the naloxone-induced increase in ethanol drinking in HA mice is mediated mainly by δ and to a lower extent by μ opioid receptors. The effect of δ-opioid receptor antagonism was abolished in HA mice carrying a C320T transition in the δ-opioid receptor gene (EU446125.1), which impairs this receptor's function. Our results indicate that high activity of the opioid system plays a protective role against ethanol dependence. Therefore, its blockage with opioid receptor antagonists may lead to a profound increase in ethanol consumption.

Seasonal Features of the Effects of Blockade of Opioid Receptors on Adaptive Behavior in Hibernating Animals

Studies of hibernating Yakutianian long-tailed ground squirrels (n = 42) addressed the effects of blockade of opioid receptors with naloxone on behavior in an open field and a holeboard chamber in the autumn (during preparation for hibernation) and in the spring (on waking at the end of hibernation). The inhibitory effects of opioid receptor blockade on systematic parameters of the overall level of CNS activation of the squirrel CNS were more marked in the autumn than in the spring. Biochemical analysis of monoamine contents revealed differences in the noradrenaline/serotonin ratio in the animals’ brains in spring and autumn. It is suggested that the interaction between the opioid and monoaminergic systems, working with a number of other factors, transfers homeostasis in hibernating animals to the new levels required both for preparation for entering hibernation – in autumn – and for transfer to the active homeothermic state – in spring.

Effect of opioid receptor blockade on acetaldehyde self-administration and ERK phosphorylation in the rat nucleus accumbens

We have previously shown that acetaldehyde (ACD), the first metabolite of ethanol, regulates its motivational properties and possesses reinforcing effects by itself. A large and still growing body of evidence indicates that the endogenous opioidergic system plays a critical role in the motivational effects of ethanol and suggests a role for extracellular signal-regulated kinase (ERK) in these effects of both ethanol and ACD. The present study was undertaken to examine if opioid-mediated mechanisms are involved in the reinforcing properties of ACD and in ACD-elicited ERK activation. To this end, Wistar rats were trained to orally self-administer ACD (0.2%) by nose poking. Responses on active nose poke caused delivery of ACD solution, whereas responses on inactive nose poke had no consequences. The effect of pretreatment with a nonselective opioid receptor antagonist, naltrexone (NTX), was evaluated during (1) maintenance of ACD self-administration, (2) deprivation effect after ACD extinction, and (3) ACD self-administration under a progressive-ratio schedule of reinforcement. Additionally, we tested the effect of NTX on saccharin (0.05%) reinforcement, as assessed by oral self-administration, and on ACD-elicited ERK phosphorylation in the nucleus accumbens (Acb), as assessed by immunohistochemistry. Finally, we examined the effect of a μ 1-selective opioid receptor antagonist, naloxonazine (NLZ), on the maintenance phase of ACD and saccharin self-administration. The results indicate that NTX (0.4–0.8 mg/kg) reduced the maintenance, the deprivation effect, and the break points of ACD self-administration without suppressing saccharin self-administration. Moreover, NTX decreased ACD-elicited ERK activation in the Acb shell and core. NLZ (10–15 mg/kg) reduced the maintenance phase of ACD self-administration without interfering with saccharin self-administration, whereas both NTX and NLZ failed to modify responses on inactive nose poke indicating the lack of a nonspecific behavioral activation. Overall, these results indicate that the opioid system is implicated in the reinforcing properties of ACD and suggest an involvement of ERK. The finding that NTX and NLZ reduce ACD but not saccharin self-administration indicates that these effects are specific to ACD.

Stress-dependent impairment of passive-avoidance memory by propranolol or naloxone

Previous work has shown that the effect of opioid-receptor blockade on memory modulation is critically dependent upon the intensity of stress. The current study determined the effect of adrenergic-receptor blockade on memory modulation under varied levels of stress and then compared the effect of adrenergic-receptor blockade under intense stress to that of a) opioid-receptor blockade and b) concurrent opioid- and adrenergic-receptor blockade. In the first experiment, the β-adrenergic-receptor blocker propranolol impaired retention in the passive-avoidance procedure when administered immediately after exposure to intense stress (passive-avoidance training followed by swim stress) but not mild stress (passive-avoidance training alone). In the second experiment, while separate administration of either propranolol or the opioid-receptor blocker naloxone immediately after exposure to intense stress impaired retention, the combined administration of propranolol and naloxone failed to do so. These findings demonstrate that the effect of β-adrenergic-receptor blockade or opioid-receptor blockade on memory modulation in the passive-avoidance procedure is dependent upon the intensity of stress, and suggest that concurrent inactivation of endogenous adrenergic- and opioid-based memory modulation systems under stressful conditions is protective of memory.

The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.

The effects of opioid receptor blockade on experimental panic provocation with CO 2

Several reports have linked, among other aspects, the role of an opioid system in respiratory physiology with underlying mechanisms of panic attacks. The involvement of the opioid system in experimental panic is to be further probed. This study aimed to determine whether opioid blockade would increase panic-related symptomatology on provocation with 35% CO2 inhaled by healthy volunteers. Participants in a double-blind, randomised crossover design orally received either 50 mg of naltrexone or placebo. Most subjects undertook a double inhalation of 35% CO2 one hour after pre-medication, and a separate group did so after five hours. The reactivity to CO2 and the symptoms elicited by naltrexone alone were measured. Among other findings, naltrexone pre-medication alone elicited significant increments in panic-related symptoms. Responses to CO2 were not significantly different between conditions in either group. These preliminary findings suggest that exposure to opioid blockade alone can potentially elicit symptoms that resemble panic, however, without modifying the response to experimental panic provocation with 35% CO2.

Effects of opioid receptor blockade on the renewal of alcohol seeking induced by context: relationship to c‐fos mRNA expression

Contextual stimuli associated with alcohol availability can induce alcohol seeking during abstinence. Using a renewal procedure, we tested the effect of opioid receptor blockade on context-induced alcohol seeking, and its relationship to the activity of brain sites involved in learning and reward. Thirty-six male Wistar rats were trained to lever press for a 12% (w/v) alcohol solution before undergoing extinction sessions (no alcohol delivery). Half of the rats underwent training, extinction and testing in a single context with a distinct set of olfactory, visual, auditory and tactile properties [training, extinction and test in Context A (AAA)]. The other half were trained and extinguished in different contexts and returned to the training context on the test day [training, extinction and test in Contexts A, B and A, respectively (ABA)]. On the test day, the rats from each condition were pre-treated with either saline or 1 mg/kg naltrexone (s.c.) and tested for alcohol seeking. Immediately following the test session, rats were killed and their brains were analysed for c-fos mRNA expression using in-situ hybridization. Re-exposure to the alcohol-associated context (ABA) significantly increased operant behaviour on the previously active lever relative to the AAA groups and this increased responding was associated with increased c-fos mRNA expression in the basal and lateral amygdala and the CA3 subregion of the hippocampus. Naltrexone pre-treatment attenuated context-induced alcohol seeking and inhibited c-fos mRNA expression in the lateral amygdala and CA3. Our findings point to a critical role for the basolateral amygdala and dorsal hippocampus in mediating context-induced renewal of alcohol seeking and suggest that opioidergic mechanisms mediate this effect.

Atypical anxiolytic-like response to naloxone in benzodiazepine-resistant 129S2/SvHsd mice: role of opioid receptor subtypes

Mice of many 129 substrains respond to environmental novelty with behavioural suppression and high levels of anxiety-like behaviour. Although resistant to conventional anxiolytics, this behavioural phenotype may involve stress-induced release of endogenous opioids. To assess the effects of opioid receptor blockade on behavioural reactions to novelty stress in a chlordiazepoxide-resistant 129 substrain. Experiment 1 contrasted the effects of the broad-spectrum opioid receptor antagonist naloxone (1.0-10.0 mg/kg) in C57BL/6JOlaHsd and 129S2/SvHsd mice exposed to the elevated plus-maze. Experiments 2-4 examined the responses of 129S2/SvHsd mice to the mu-selective opioid receptor antagonist beta-funaltrexamine (2.5-10.0 mg/kg), the delta-selective antagonist naltrindole (2.5-10.0 mg/kg) and the kappa-selective antagonist nor-binaltorphimine (2.5-5.0 mg/kg). 129 mice displayed higher levels of anxiety-like behaviour and lower levels of general exploration relative to their C57 counterparts. Although naloxone failed to alter the behaviour of C57 mice, both doses of this antagonist produced behaviourally selective reductions in open-arm avoidance in 129 mice. Surprisingly, none of the more selective opioid receptor antagonists replicated this effect of naloxone: beta-funaltrexamine was devoid of behavioural activity, naltrindole suppressed rearing (all doses) and increased immobility (10 mg/kg), while nor-binaltorphimine (5 mg/kg) nonspecifically increased percent open arm entries. Recent evidence suggests differential involvement of opioid receptor subtypes in the anxiolytic efficacy of diverse compounds including conventional benzodiazepines. The insensitivity of 129 mice to the anxiolytic action of chlordiazepoxide, coupled with their atypical anxiolytic response to naloxone (but not more selective opioid receptor antagonists), suggests an abnormality in anxiety-related neurocircuitry involving opioid-GABA interactions.

Naloxone depresses cocaine self-administration and delays its initiation on the following day.

While dopamine mechanisms play a crucial role in cocaine-taking behavior, the contribution of endogenous opioid systems is less clear. We assessed the effects of opioid receptor blockade by naloxone (1 mg/kg, s.c.) on the daily performance and subsequent initiation of cocaine self-administration in trained rats. Naloxone decreased self-administration rate by approximately half, with the effect varying from complete blockade to no change. On the day following naloxone treatment, the latencies from the drug availability cue to the first self-administration were consistently longer than before naloxone treatment. Measurement of brain temperature and behavioral observations suggested a lower than normal level of motivational arousal as a factor for slow initiation of cocaine-taking behavior. After the first drug infusion, however, performance was uniformly normal. These data suggest endogenous opioid systems play a role in cocaine-taking behavior and indicate a residual inhibitory consequence of naloxone treatment on the initiation of this behavior.

Effects of opioid receptor blockade on defensive behavior elicited by electrical stimulation of the aversive substrates of the inferior colliculus in Rattus norvegicus (Rodentia, Muridae).

Electrical or chemical stimulation of some structures of the midbrain tectum, such as the dorsal periaqueductal gray matter, deep layers of the superior colliculus and inferior colliculus induce fear and flight behavior. These structures constitute the main neural substrates commanding defensive behavior in brainstem. Many neurotransmitters are implicated in the modulation of aversion at the mesencephalic level. The aim of this work is to investigate the involvement of opioid mechanisms in modulation of defensive behavior in dorsal mesencephalon. Male Wistar rats were fixed in a stereotaxic frame and a chemitrode was implanted into the midbrain, targeted to the central nucleus of the inferior colliculus. In the present study, the effects of peripheral and central administration of naloxone, naltrexone or naloxonazine on aversive thresholds (freezing and escape reactions) elicited by electrical stimulation of the midbrain tectum were determined. Peripherally and centrally administered naloxone caused a significant increase in the freezing and flight thresholds elicited by electrical stimulation of the aversive substrates of the inferior colliculus. These effects were confirmed by peripheral and central administration of naltrexone and by microinjections of naloxonazine in inferior colliculus. These findings suggest that endogenous opioids are involved in the modulation of the aversive behavior elicited by midbrain tectum stimulation. Since microinjections of naloxonazine in the central nucleus of the inferior colliculus caused a significant increase in the aversive thresholds elicited by electrical stimulation of this structure, it is possible that micro1 opioid receptor located in this nucleus may be critically implicated in this neural circuitry.

Effect of naloxone on immune responses after hemorrhagic shock.

To determine whether naloxone administration after hemorrhagic shock has any beneficial or deleterious effect on immune responses. Hemorrhagic shock is known to produce immunodepression in both humans and experimental animals. Although studies suggest that endogenous opioids play a role in immune regulation in adverse circulatory conditions, it remains controversial whether these opioids exert beneficial or detrimental effects on immunity after shock. Moreover, little information is available concerning the effects of opioid receptor blockade using naloxone on cell-mediated immunity and endocrine responses after shock. Male C3H/HeN mice (25 g) were bled to and maintained at a mean arterial blood pressure of 35+/-5 mm Hg for 1 hr. The shed blood was then returned along with lactated Ringer's solution (two times the shed blood volume) to provide fluid resuscitation. The animals were randomized to receive either naloxone (1 mg/kg i.v.) or an equal volume of vehicle (saline) after the shed blood was returned, i.e., immediately before crystalloid resuscitation, and were killed at 2 hrs after resuscitation to obtain splenocytes, macrophages (peritoneal and splenic), and blood. Bioassays revealed significantly decreased release of all studied interleukins (interleukins-1, -2, -3, and -6) by peritoneal and splenic macrophages as well as significantly decreased splenocyte proliferative capacity after shock in vehicle-treated mice. Naloxone administration after hemorrhage resulted in either similar or even more decreased levels of interleukin release compared with vehicle-treated hemorrhaged mice. Significantly increased plasma corticosterone concentrations were observed in vehicle-treated animals compared with control animals. Naloxone administration did not have any significant effects on corticosterone plasma concentrations after hemorrhage. These findings indicate the importance of the endogenous opioid system for the maintenance of immunity in adverse circulatory conditions, i.e., hemorrhage. Although additional studies involving different doses and/or times of naloxone administration may provide different results, the present findings raise the concern that naloxone administration in the traumatized host may have deleterious effects because it decreases peritoneal macrophage and splenic immune functions.

Opioidergic modulation of spinal reflexes activated by mechanical stimulation of the heel in the decerebrated, spinalized rabbit.

The effects of opioid receptor blockade on reflex responses elicited in medial gastrocnemius and semitendinosus motor nerves by controlled mechanical stimulation of the skin over the heel have been investigated in decerebrated, spinalized rabbits. Pinch forces of 173 mN, 561 mN (light touch), 1642 mN (firm pinch) and 4632 mN (firm to painful) were used. In the control state, background activity was absent from gastrocnemius motoneurones and low in semitendinosus. Pinches of 561 mN and above evoked brisk reflexes in gastrocnemius motoneurones, whereas delayed responses (median latency 1 s) were elicited in semitendinosus by pinches of 1642 mN and 4632 mN. Intravenous administration of the non-selective opioid receptor antagonist (-)-quadazocine (1-781 microg kg(-1)) dose-dependently and stereospecifically increased background activity and enhanced reflex responses to all pinch strengths in both medial gastrocnemius and semitendinosus muscle nerves. Pinches of 173 mN became reflexogenic and higher intensity stimuli evoked significantly larger responses than in the control state. These findings show that tonic opioidergic inhibition in rabbit spinal cord is wide-spread and non-selective, having a powerful influence on transmission of signals to motoneurones from high- and low-threshold cutaneous afferents.

Relaxation training and opioid inhibition of blood pressure response to stress.

The present study was designed to determine the role of endogenous opioid mechanisms in the circulatory effects of relaxation training. Opioid mechanisms were assessed by examination of the effects of opioid receptor blockade with naltrexone on acute cardiovascular reactivity to laboratory stress before and after relaxation training. Thirty-two young men with mildly elevated casual arterial pressure were recruited for placebo-controlled naltrexone stress tests and relaxation training. The results indicated that relaxation training significantly reduced the diastolic pressure response to mental arithmetic stress. Opioid receptor blockade with naltrexone antagonized the effects of relaxation training. These findings suggest that some of the physiological effects of relaxation training are mediated by augmentation of inhibitory opioid mechanisms.

Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients.

The aim of this study was to assess the possibility that ovulation might be induced in seven amenorrheic hyperprolactinemic women by treatment with naltrexone (50 mg/day) for 4-5 weeks. None of the patients ovulated. Increases in LH levels, LH area under the curve, FSH levels, and the number of LH pulses per 6 h were observed in all patients, 2-8 h after the beginning of naltrexone administration. However, all of these parameters had returned to the pretreatment range on day 7. The LH area under the curve, LH levels, FSH levels, and the number of LH pulses per 6 h on day 1 were significantly higher compared to the values on either day 0 (basal levels) or day 7. These data show that long term opioid receptor blockade induces desensitization of the hypothalamic-pituitary unit for the effects of opioid receptor blockade. Due to the induced desensitization, naltrexone is not an effective drug for ovulation induction in hyperprolactinemic patients.

Effects of opioid receptor blockade on the social behavior of rhesus monkeys living in large family groups

Rhesus monkeys of 9 weeks, 48 weeks, 100 weeks, 150 weeks of age (young subjects), or mature parous females that were not lactating were given acute single doses of the opioid antagonist naloxone (0.5 mg/kg) and vehicle on different days and observed in their familial social groups. Naloxone increased the occurrence of affiliative behaviours. Young subjects spent more time in contact with their mothers but showed no changes in social grooming. Maternal contact was actively sought through contact vocalizations, decreasing proximity, and, for the youngest infants, increased attempts to suckle. Mature females made more solicitations for grooming and received more grooming from their companions. These results are interpreted in terms of naloxone blocking the positive effect arising from social contact and thus causing subjects to seek further affiliative comfort.

Do endogenous opioids mediate the relationship between blood pressure and pain sensitivity in normotensives?

Elevated resting blood pressure is associated with decreased pain sensitivity in both animals and humans. Recent evidence suggests that this relationship may be mediated by endogenous opioid peptides in hypertensives, but the precise mechanism has not been investigated in normotensives. We examined the effect of opioid receptor blockade with naloxone on the relationship between resting blood pressure and pain sensitivity in normotensive humans. Sixteen young adults were given cold pressor and handgrip challenges after treatment with either naloxone or saline in a placebo-controlled, within-subject design. Multiple regression procedures indicated that resting systolic blood pressure was a significant predictor of cold pain ratings even after the effects of naloxone were statistically controlled. The interaction between systolic blood pressure and opioid blockade was non-significant. These data suggest that the relationship between resting blood pressure and pain sensitivity in normotensive humans is mediated, at least in part, by non-opioid mechanisms.

Effects of opioid receptor blockade on luteinizing hormone (LH) pulses and interpulse LH concentrations in normal women during the early phase of the menstrual cycle.

To determine the role of endogenous opioid peptides in regulating pulsatile luteinizing hormone (LH) release in the early follicular phase of the menstrual cycle of eumenorrheic women, we evaluated serum LH concentrations in blood collected every 10 min for 12 h in 27 women each studied during two menstrual cycles: (1) without pretreatment and (2) following oral administration of naltrexone, a mu opiate receptor blocking agent, at a dose of 1.0 mg/kg. Pulsatile LH release was assessed by the CLUSTER algorithm. The mean (+/- SE) integrated serum LH concentration (IU/L/min) increased following the administration of naltrexone (4715 +/- 298) in comparison to the control day (3997 +/- 381; p = 0.0008). The mean number of LH pulses (/12 h) detected on the naltrexone day (10.3 +/- 0.3) was higher than on the control day (8.9 +/- 0.4; p = 0.0068). Mean maximal LH peak height (IU/L) was greater on the naltrexone (7.8 +/- 0.5) vs control (6.7 +/- 0.5) days (p = 0.0064) as was the interpulse valley mean serum LH concentration (IU/L; 6.3 +/- 0.4 vs 5.0 +/- 0.4; p = 0.0013). No difference was noted in the mean incremental LH pulse amplitude (IU/L; 1.9 +/- 0.1 vs 2.1 +/- 0.1; p = 0.13), or peak duration (min; 40 +/- 1.8 vs 45.0 +/- 2.4; p = 0.06). Mean LH peak area (IU/L/min) was greater on the control (45.0 +/- 2.4) vs naltrexone (40 +/- 1.8) days (p = 0.0475).(ABSTRACT TRUNCATED AT 250 WORDS)