Opioid Receptor Blockade Research Articles

Kinin and opioid receptors in the paratrigeminal nucleus modulate the somatosensory reflex to rat sciatic nerve stimulation

The influence of kinin and opioid receptor blockade in the paratrigeminal nucleus (Pa5) on the somatosensory reflex (SSR) to sciatic nerve stimulation (SNS) was assessed in anaesthetized–paralyzed rats. SNS (square 1 ms pulses at 0.6 mA and 20 Hz for 10 s) increased mean arterial pressure from 87 ± 3 to 106 ± 3 mmHg. Pressor responses to SNS were reduced 40–60% by HOE-140 and LF 16-0687 (B 2 receptor antagonists; 20 and 100 pmol respectively), CTOP or nor-binaltorphimine (mu and kappa opioid receptor antagonists, respectively; 1 μg) but potentiated by naltrindole (delta opioid receptor antagonist) receptor antagonist microinjections into the contralateral (but not ipsilateral) Pa5. The SSR to sciatic nerve stimulation was not changed by B 1 kinin receptor or NK 1, NK 2 and NK 3 tachykinin receptor antagonists administered to the Pa5. Capsaicin pretreatment (40 mg/kg/day, 3 days) abolished the effects of the opioid receptor antagonists, but did not change the effect of kinin B 2 receptor blockade on the SSR. Thus, the activity of B 2 and opioid receptor-operated mechanisms in the Pa5 contribute to the SSR in the rat, suggesting a role for these endogenous peptides in the cardiovascular responses to SNS.

Reinstatement of cocaine-seeking behavior in rats is attenuated following repeated treatment with the opioid receptor antagonist naltrexone

In the present study we show that the endogenous opioid systems play a modulating role in cocaine-induced reinstatement of drug-seeking behavior in rats. We investigated the effect of blockade of opioid receptors on reinstatement of cocaine-seeking behavior by cocaine priming. Drug-naive rats were allowed to initiate self-administration behavior of cocaine (30 and 60 mug per infusion, i.v.) for 5 consecutive daily sessions, and after a 5-day extinction period during which the rats did not receive cocaine, a test for cocaine-induced (1 mg/kg, i.v.) reinstatement followed. The effect of cocaine priming was tested on days 1, 3, and 5 after extinction, while on days 2 and 4 the animals received saline priming. Before each daily reinstatement test, different groups of animals received an injection with the opioid receptor antagonist naltrexone (3 mg/kg, s.c.) or with placebo. We observed that cocaine readily reinstated extinguished responding in the rats, and that this reinstatement responding did not change over the consecutive reinstatement tests. Pretreatment with naltrexone progressively attenuates the cocaine-induced reinstatement, with a significant reduction on days 3 and 5 of reinstatement testing. Discriminative lever-pressing (active versus inactive lever) during reinstatement phase, however, remains present in animals treated with naltrexone. This implies that repeated opioid receptor blockade progressively attenuates cocaine-induced drug-seeking behavior in abstained animals, but this cannot simply be attributed to extinction of cocaine-seeking behavior.

Inotropic effect of Citrus sinensis (L.) Osbeck leaf extracts on the guinea pig atrium

The objective of the present investigation was to determine the contractile effect of crude and acetone leaf extracts of Citrus sinensis (L.) Osb. on mammalian myocardium. Crude leaf extracts have been used in folk medicine to treat neurological disorders. Some flavonoids isolated from this plant presented a positive inotropic effect on myocardium. This motivated us to test the extracts on the atria of guinea pigs of both sexes (300-500 g) and surprisingly we observed inotropic depression instead of an increase in force. The maximum effect of the crude extract was 79.4 +/- 8.1% of the control force amplitude (N = 5 hearts, 10 trials, 27 +/- 0.1 degrees C, stimulus: 2 Hz, 400 V, 0.5 ms). The EC50 for crude, ethanol, acetic, aqueous, and acetone extracts was 300, 300, 600, 1000, and 140 microg/ml, respectively, with a Hill constant of 1.8, 2.0, 2.5, 2.0, and 1.4, respectively. Blockade of cholinergic, beta-adrenergic, or opioid membrane receptors with 1.5 microM atropine sulfate, 1 microM propranolol, and 10 microM naloxone, respectively, did not change the effect of the crude extract. The acetone extract abolished the Bowditch positive staircase phenomenon (N = 5 hearts, 10 trials, 27 +/- 0.1 degrees C), suggesting a possible reduction of the calcium inward current, and also promoted the so-called Woodworth phenomenon. The effect was concentration-dependent and indicated the existence of another inhibitory contractile mechanism such as the simultaneous activation of some of the membrane potassium channels reducing the myocardial action potential duration and further decreasing the cellular calcium entry.

Shock Induction by Arterial Hypoperfusion of the Gut Involves Synergistic Interactions between the Peripheral Enkephalin and Nitric Oxide Systems

To determine whether critical splanchnic artery hypoperfusion can provoke systemic shock and to identify the roles of the peripheral opioid and nitric oxide (NO) systems in this process, various degrees of superior mesenteric artery hypoperfusion (SMA-H) were produced in anesthetized adult rabbits (n=40), and hemodynamic and metabolic indices were measured. Metabolic acidosis and irreversible hypodynamic shock occurred with SMA-H at levels representing 25-20% of mean baseline SMA blood flow. In 112 other rabbits subjected to SMA-H at 20% (SMA-H20%), we studied plasma NO and enkephalin (ENK) levels, cardiovascular reactivity to selected physiological agonists, effects of ENKs on plasma NO levels, and effects of peripheral opioid receptor blockade and inducible NO synthase (iNOS) inhibition. SMA-H20% progressively increased systemic blood levels of NO and ENKs. Exogenous ENK administration accentuated SMA-H20%-induced increases in plasma NO levels, and their cardiovascular depressing effects were significantly greater when they were administered during SMA-H20% (vs. administration under baseline conditions). Selective blockade of cardiovascular delta-opioid receptors improved hemodynamics, prevented shock irreversibility and reduced plasma NO levels; similar effects were obtained by selective iNOS inhibition. These findings demonstrate that critical arterial hypoperfusion of the gut can induce hypodynamic systemic shock through ENK-induced hyperactivation of cardiovascular delta-opioid receptors, which leads to increased plasma levels of NO related in part to increased iNOS activity. Since pronounced splanchnic artery hypoperfusion occurs in all advanced systemic shock states, selective delta-opioid receptor antagonists and/or iNOS inhibitors may prove to be useful in improving shock hemodynamics and metabolic derangements and/or preventing progression toward irreversibility.

Opioid receptor blockade reduces Fas-induced hepatitis in mice.

Fas (CD95)-induced hepatocyte apoptosis and cytotoxic activity of neutrophils infiltrating the injured liver are two major events leading to hepatitis. Because it has been reported that opioids, via a direct interaction, sensitize splenocytes to Fas-mediated apoptosis by upregulating Fas messenger RNA (mRNA) and modulated neutrophil activity, we assumed that opioids may participate in the pathophysiology of hepatitis. Using the hepatitis model induced by agonistic anti-Fas antibody in mice, we showed that opioid receptor blockade reduced liver damage and consequently increased the survival rate of animals when the antagonist naltrexone was injected simultaneously or prior to antibody administration. Treatment of mice with morphine enhanced mortality. Naloxone methiodide-a selective peripheral opioid antagonist-had a protective effect, but the absence of opioid receptors in the liver, together with lack of morphine effect in Fas-induced apoptosis of primary cultured hepatocytes, ruled out a direct effect of opioids on hepatocytes. In addition, the neutralization of opioid activity by naltrexone did not modify Fas mRNA expression in the liver as assessed with real-time quantitative polymerase chain reaction. Injured livers were infiltrated by neutrophils, but granulocyte-depleted mice were not protected against the enhancing apoptotic effect of morphine. In conclusion, opioid receptor blockade improves the resistance of mice to Fas-induced hepatitis via a peripheral mechanism that does not involve a down-modulation of Fas mRNA in hepatocytes nor a decrease in proinflammatory activity of neutrophils.

Comprehensive mu-opioid-receptor genotyping by pyrosequencing.

The human μ-opioid receptor, encoded by the OPRM1 gene (1)(2), is the major site for the analgesic action of opioids. The OPRM1 gene is therefore a first-line candidate for evaluating the role of mutations on the clinical effects of opioids. The mutant allele of the 118A>G single-nucleotide polymorphism (SNP) in the OPRM1 gene, which codes for an Asn40Asp μ-opioid receptor, has been associated with decreased opioid activity in carriers of the 118G allele. Morphine 6-glucuronide (M6G) and morphine have lower potencies for pupil constriction in carriers of the mutation, who also vomit less often after treatment with M6G than noncarriers (3). Carriers of the 118G allele need more alfentanil for postoperative analgesia but have less pain relief than noncarriers (4). The 118G allele has also been associated with a greater cortisol response to opioid receptor blockade with naloxone (5). Regarding opioid addiction, the mutant allele of the 17C>T SNP was found more frequently in drug addicts than in nonaddicts (6)(7). An association between the mutant alleles of the 118A>G (exon 1) and 691C>G (intron 2) SNPs and opioid dependence was reported for Chinese heroin addicts, although this was based on a small study group (8). The frequency of the mutated 118G allele was higher in Indian heroin addicts than in controls (9). Addicted individuals carrying both the mutated 118G allele and the mutated 31A allele in intron 2 consumed higher doses of heroin than individuals who did not carry these mutations (10). The simultaneous presence of the mutated alleles for SNPs −1793T>A, −1699-(−1698)insT, −1320A>G, −111C>T, and 17C>T is associated with substance dependence (11). In European Americans, allele −2044A and haplotypes that include −2044A were found to be associated with susceptibility for substance dependence (12). To promote further investigation of an association of OPRM1 mutations …

1st International Conference on Panic Attacks: diversity of theories and treatments

The 1st International Conference on Psychophysiology of Panic Attacks focused on the diversity of treatments and theories in this complex condition. Experimental research topics were featured, as well as treatment strategies, case studies and patient perspectives. The conference aimed to create a strong multi-cultural emphasis through international, interdisciplinary and patient–professional interaction. The experimental techniques of lactate provocation of panic, carbon dioxide provocation, respiratory measures and cholecystokinin tetrapeptide infusion were used in various ongoing studies aimed at investigating familial markers, protocols for inducing panic in subjects (including opioid-receptor blockade), brain stem mechanisms involved in mediating anxiety and correlation of respiratory variability with panic severity and treatment outcome. Internet-based questionnaire surveys of panic attack (PA) in subjects that had been sexually abused and of subjective feelings about PAs in patients undergoing fertility treatment were presented, as was a survey of panic epidemiology in Iranian students. Some novel treatment modes were discussed, including non-verbal imagery and art therapy and a telephone-conferencing delivery of cognitive-behavioural therapy. Several case studies were used to illustrate treatments and a personal account of panic disorder combined some time after onset with post-traumatic stress disorder highlighted the different responses of the two disorders to psychotherapies.

Neurophysiology of pruritus: interaction of itch and pain.

The discovery of an itch-specific neuronal pathway, which is distinct from the pain-processing pathway, has clarified the neuronal basis for the itch sensation. Albeit being distinct, there are complex interactions between pain and itch. The inhibition of itch by pain is well known and can explain the antipruritic effect of scratching. However, the opposite effect also exists and has major clinical implications: inhibition of pain processing (eg, by spinal opioids) can generate itch. Conversely, blockade of spinal opioid receptors can be used as an antipruritic therapy. Moreover, the spinal processing of pain and itch can be modulated, resulting in a hypersensitivity or hyposensitivity to pain or itch: similar to chronic painful conditions, ongoing activity of pruriceptors can induce a spinal hypersensitivity for itch in patients with chronic pruritus. Therapeutic antipruritic approaches therefore should target both local inflammation and spinal sensitization of itch processing.

Use of Anesthesia-assisted Detoxification in the Opioid-dependent Pain Patient

In Reply:—We appreciate Dr. Gourlay's interest in our work. 1Of course, we are aware that clonidine, while diminishing sympathetic neural outflow both in volunteers 2and in opioid addicts, 3,4acts as an agonist on central α-receptors. We apologize for the typographical error that appears on page 571 of the original article.We agree that antagonist supported detoxification from opioids during general anesthesia can restore opioid sensitivity. Accordingly, opioid receptor blockade, e.g. , by oral naltrexone, should be maintained in formerly addicted patients as long as possible to prevent both relapses as well as potentially fatal effects of further opioid intake. However, our patient experienced chronic pain with tolerance to the analgetic effects of administered opioids. Thus, antagonist supported detoxification was intended to restore opioid sensitivity, allowing continuation of analgesic therapy by administration of much lower opioid dosages while again achieving sufficient analgesia.With respect to cost–benefit ratios, we expect by this procedure high rates of successful detoxification with markedly shortened hospitalization. 5,6Accordingly, this procedure seems to be economically attractive. However, a decrease in the number of relapses may not be expected, although little data are currently available.

The expression and function of the OGF–OGFr axis – a tonically active negative regulator of growth – in COS cells

This study was designed to examine the presence and role of the opioid growth factor (OGF, [Met 5]-enkephalin) and the OGF receptor (OGFr) in COS-7 cells; these cells lack classical opioid receptors. Preproenkephalin mRNA, which encodes OGF, was detected by Northern blot analysis, and OGFr mRNA was recorded by RT-PCR. Receptor binding analysis showed specific and saturable binding ( K d=3.5 nm, B max=44 fmol/mg protein) for OGFr in the nuclear fraction. Both OGF and OGFr were recorded in COS-7 cells by immunocytochemistry. Addition of OGF to log-phase COS-7 cultures depressed growth by 41.6% from control levels, whereas opioid-receptor blockade by the opioid antagonist, naltrexone, increased the number of cells by 29.8% from control values. The effect of OGF was receptor mediated. Exposure to a wide variety of synthetic and natural opioid peptides, including those selective for μ, δ, and κ opioid receptors, showed that only OGF had an effect. Treatment with antisense OGFr oligonucleotides increased the number of cells by over 2-fold compared to wild-type cultures of COS-7 cells and preparations receiving scrambled oligonucleotides. These results indicate that the OGF–OGFr axis is present and functions in COS-7 cells, and in the absence of classical opioid receptors.

Local μ and δ opioid receptors regulate amphetamine-induced behavior and neuropeptide mRNA in the striatum

The purpose of this study was to investigate the role that μ and δ opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the μ opioid antagonist, H- d-Phe-Cys-Tyr- d-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), or the δ opioid antagonist, H-Tyr-Tic[CH 2NH]-Phe-Phe-OH (TIPPψ), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPψ significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both μ and δ receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.

Sustained exogenous administration of Met5-enkephalin protects against infarction in vivo.

The opioid antagonist naloxone abolishes infarct limitation by myocardial ischemic preconditioning, suggesting that one or more endogenous opioid peptides can mediate cardiac protection against ischemic damage. We tested the hypothesis that the naturally occurring opioid peptide Met5-enkephalin (ME) modulates myocardial infarct size in vivo. Experiments were conducted in barbiturate-anesthetized open-chest rabbits subjected to regional myocardial ischemia-reperfusion. ME was administered via osmotic minipump for 24 h. Infarct size was assessed with tetrazolium and is expressed as a percentage of the area at risk. Exogenous ME reduced the amount of the risk zone infarcted by approximately 60% compared with saline-treated controls. ME-induced protection was sensitive to opioid receptor blockade with naloxone [NAL 50 +/- 2% vs. ME + NAL 39 +/- 3%, P = not significant (NS)] and also to blockade of sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels [5-hydroxydecanoate (5-HD) 33 +/- 3% vs. ME + 5-HD 43 +/- 8%, P = NS; and HMR-1098 60 +/- 3% vs. ME + HMR-1098 54 +/- 7%, P = NS]. We conclude that ME limits ischemic injury in vivo by an opioid receptor-mediated mechanism that involves both sarcolemmal and mitochondrial KATP channels.

Opioid growth factor (OGF) inhibits the progression of human squamous cell carcinoma of the head and neck transplanted into nude mice.

Opioid growth factor (OGF) interacts with the OGF receptor (OGFr) and serves as a native inhibitory growth factor. OGF and OGFr are present in squamous cell carcinoma of the head and neck (SCCHN), and OGF represses the replication of SCCHN in tissue culture. In this study, OGF-treated nude mice with xenografts of SCCHN displayed delays in tumor appearance and had reduced tumor size compared to controls. OGF activity was receptor-mediated. Opioid-receptor blockade by the potent opioid antagonist, naltrexone, stimulated tumorigenic processes. Both OGF and OGFr were detected in the tumors by immunohistochemistry, and OGFr was characterized by receptor binding analysis. These results indicate that the OGF-OGFr axis functions in vivo, OGF is a constitutively active molecule, and OGF modulation of SCCHN may have clinical application.

Quantitative autoradiography of adenosine receptors in brains of chronic naltrexone-treated mice.

1. Manipulation of micro opioid receptor expression either by chronic morphine treatment or by deletion of the gene encoding micro opioid receptors leads to changes in adenosine receptor expression. Chronic administration of the opioid receptor antagonist naltrexone leads to upregulation of micro receptor binding in the brain. 2. To investigate if there are any compensatory alterations in adenosine systems in the brains of chronic naltrexone-treated mice, we carried out quantitative autoradiographic mapping of A(1) and A(2A) adenosine receptors in the brains of mice treated for 1 week with naltrexone (8 mg(-1) kg(-1) day(-1)), administered subcutaneously via osmotic minipump. 3. Adjacent coronal brain sections were cut from chronic saline- and naltrexone-treated mice for the determination of binding of [(3)H] D-Ala(2)-MePhe(4)-Gly-ol(5) enkephalin ([(3)H] DAMGO), [(3)H]1,3-dipropyl-8-cyclopentylxanthine ([(3)H] DPCPX) or [(3)H] 2-[p-(2-carbonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine ([(3)H] CGS21680) to micro, A(1) and A(2A) receptors, respectively. 4. A significant increase in micro and A(1) receptor binding was detected in chronic naltrexone-treated brains. The changes in micro receptors were significant in several regions, but changes in A(1) were relatively smaller but showed significant upregulation collectively. No significant change in A(2A) receptor binding was detected in chronic naltrexone-treated brains. 5. The results show that blockade of opioid receptors causes upregulation of A(1) receptors, but not A(2A) receptors, by as yet undefined mechanisms.

Blockade of ventral pallidal opioid receptors induces a conditioned place aversion and attenuates acquisition of cocaine place preference in the rat

Peripheral administration of naloxone is known to produce a conditioned place aversion and to block cocaine-induced conditioned place preference. The ventral pallidum receives a dense enkephalinergic projection from the nucleus accumbens and is implicated as a locus mediating the rewarding and reinforcing effects of psychostimulant and opiate drugs. We sought to provide evidence for the involvement of pallidal opioid receptors in modulating affective state using the place-conditioning paradigm. Microinjection of naloxone (0.01–10 μg) into the ventral pallidum once a day for 3 days dose-dependently produced a conditioned place aversion when tested in the drug-free state 24 h after the last naloxone injection. This effect was reproduced using the μ-opioid receptor selective agonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP, 1 μg). Locomotor activity was reduced following injection of the highest dose of naloxone (10 μg) but elevated following CTOP (1 μg). Daily injection of cocaine (10 mg/kg) for 3 days produced a conditioned place preference 24 h later. This effect of cocaine was attenuated by concomitant intra-ventral pallidal injection of naloxone at a dose (0.01 μg) that had no significant aversive property when injected alone. In contrast, the locomotor activation induced by peripheral cocaine injection was unaffected by naloxone injection into the ventral pallidum. The data implicate endogenous opioid peptide systems within the ventral pallidum as regulators of hedonic status.

Receptor-selective changes in mu-, delta- and kappa-opioid receptors after chronic naltrexone treatment in mice.

Chronic treatment with the opioid antagonist naltrexone induces functional supersensitivity to opioid agonists, which may be explained by receptor up-regulation induced by opioid receptor blockade. In the present study, the levels of opioid receptor subtypes through the brain of mice were determined after chronic naltrexone treatment using quantitative in vitro autoradiography. This is the first complete mapping study in mice for micro-, delta- and kappa-opioid receptors after chronic naltrexone exposure. Treatment with naltrexone clearly induced up-regulation of micro- (mean 80%) and, to a lesser extent, delta-opioid receptors (mean 39%). The up-regulation of micro- and delta-opioid receptors was evident throughout the brain, although there was variation in the percentage change across brain regions. In contrast, consistent up-regulation of kappa-opioid receptors was observed in cortical structures only and was not so marked as for micro- and delta-opioid receptors. In noncortical regions kappa-opioid receptor expression was unchanged. Taken together, the present findings suggest opioid receptor subtype-selective regulation by chronic naltrexone treatment in mice.

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.

Dynorphin A (1–17) induces apoptosis in striatal neurons in vitro through α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome C release and caspase-3 activation

Dynorphin A (1–17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1–17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl- d-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (−)-naloxone, a general opioid antagonist. The results show that dynorphin A (1–17) (≥10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors.

Participation of endogenous opioids in pathogenesis of early neuroendocrine manifestations of prenatal stress syndrome.

We studied sex dimorphism in the content of norepinephrine and activity of enzymes involved in testosterone metabolism in the preoptic hypothalamic area of 10-day-old rats. Prenatal stress eliminated sex-related differences in these indices. These disturbances were absent in rats subjected to prenatal stress under conditions of opioid receptor blockade with naltrexone. These data attests to the important role of opioids in the pathogenesis of prenatal stress syndrome.

μ-Opioid Receptor-Mediated Antinociceptive Responses Differ in Men and Women

Sex differences in the experience of clinical and experimental pain have been reported. However, the neurobiological sources underlying the variability in pain responses between sexes have not been adequately explored, especially in humans. The endogenous opioid neurotransmitters and mu-opioid receptors are centrally implicated in responses to stress, in the suppression of pain, and in the action of opiate analgesic drugs. Here we examined sex differences in the activation of the mu-opioid system in response to an intensity-controlled sustained deep-tissue pain challenge with positron emission tomography and a mu-opioid receptor-selective radiotracer. Twenty-eight young healthy volunteers (14 men and 14 women) were studied during saline control and pain conditions using a double-blind, randomized, and counterbalanced design. Women were scanned during the early follicular phase of their menstrual cycles after ovulatory cycles. Significant sex differences in the regional activation of the mu-opioid system in response to sustained pain were detected compared with saline controls. Men demonstrated larger magnitudes of mu-opioid system activation than women in the anterior thalamus, ventral basal ganglia, and amygdala. Conversely, women demonstrated reductions in the basal state of activation of the mu-opioid system during pain in the nucleus accumbens, an area previously associated with hyperalgesic responses to the blockade of opioid receptors in experimental animals. These data demonstrate that at matched levels of pain intensity, men and women during their follicular phase differ in the magnitude and direction of response of the mu-opioid system in distinct brain nuclei.