Consequences of Parental Opioid Exposure on Neurophysiology, Behavior, and Health in the Next Generations.

Substance abuse and the ongoing opioid epidemic represents a large societal burden. This review will consider the long-term impact of opioid exposure on future generations. Prenatal, perinatal, and preconception exposure are reviewed with discussion of both maternal and paternal influences. Opioid exposure can have long-lasting effects on reproductive function, gametogenesis, and germline epigenetic programming, which can influence embryogenesis and alter the developmental trajectory of progeny. The potential mechanisms by which preconception maternal and paternal opioid exposure produce deleterious consequences on the health, behavior, and physiology of offspring that have been identified by clinical and animal studies will be discussed. The timing, nature, dosing, and duration of prenatal opioid exposure combined with other important environmental considerations influence the extent to which these manipulations affect parents and their progeny. Epigenetic inheritance refers to the transmission of environmental insults across generations via mechanisms independent of the DNA sequence. This topic will be further explored in the context of prenatal, perinatal, and preconception opioid exposure for both the maternal and paternal lineage.

Differential expression of µ-opioid receptors in the nucleus accumbens, amygdala and VTA depends on liking for alcohol, chronic alcohol intake and estradiol treatment.

Affectations of the opioid system have been related to exacerbated alcohol consumption. The objectives of this work were to assess whether a deficit of ß-endorphinergic neurons differentially affects alcohol intake in female rats with low (LC) and high alcohol consumption (HC), and to determine changes in the µ-opioid receptors (MOR) related to alcohol consumption and chronic exposure to alcohol in structures of the mesolimbic system. Female wild-type rats were selected according to their baseline alcohol intake levels and then exposed to chronic voluntary alcohol consumption after a single injection of either the vehicle or estradiol valerate (EV) to produce a ß-endorphin neuronal deficit. Changes in alcohol consumption and MOR expression levels were assessed in the nucleus accumbens (NAc), amygdala (Amy) and ventral tegmental area (VTA) at 5 and 10 weeks after EV treatment. The LC rats increased alcohol intake from baseline to the initial weeks after EV treatment and this consumption remained stable throughout the studied period. In contrast, alcohol consumption increased steadily over time in the HC rats. The HC vehicle rats had a 38% higher MOR protein expression in the NAc than the LC vehicle rats. In addition, chronic alcohol consumption increased MOR expression in the Amy regardless of consumption level, whereas EV treatment produced a decrease in MOR expression in the VTA in all groups. These results suggest intrinsic differences in MOR expression related to alcohol consumption levels. Also, the EV treatment and chronic exposure to alcohol produced adaptive changes in MOR expression.

Extremely low frequency magnetic fields can either increase or decrease analgaesia in the land snail depending on field and light conditions.

Results of prior investigations with opioid peptide mediated antinociception or analgaesia have suggested that these extremely low frequency (ELF) magnetic field effects are described by a resonance mechanism rather than mechanisms based on either induced currents or magnetite. Here we show that ELF magnetic fields (141-414 microT peak) can, in a manner consistent with the predictions of Lednev's parametric resonance model (PRM) for the calcium ion, either (i) reduce, (ii) have no effect on, or (iii) increase endogenous opioid mediated analgaesia in the land snail, Cepaea nemoralis. When the magnetic fields were set to parameters for the predictions of the PRM for the potassium ion, opioid-peptide mediated analgaesia increased and there was evidence of antagonism by the K(+) channel blocker, glibenclamide. Furthermore, these effects were dependent on the presence of light; the effects were absent in the absence of light. These observed increases and decreases in opioid analgaesia are largely consistent with the predictions of Lednev's PRM.

Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP55,940, Delta(9)-THC and anandamide.

The endogenous opioid dynorphin B was evaluated for its role in cannabinoid-induced antinociception. Previous work in our laboratory has shown that the synthetic, bicyclic cannabinoid, CP55,940, induces the release of dynorphin B whilst the naturally occurring cannabinoid, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), releases dynorphin A. The dynorphins contribute in part to the antinociceptive effects of both cannabinoids at the level of the spinal cord. The present study compares dynorphin B released from perfused rat spinal cord in response to acute administration of anandamide (AEA), Delta(9)-THC and CP55,940 at two time points, 10 min and 30 min post administration, and attempts to correlate such release with antinociceptive effects of the drugs. Dynorphin B was collected from spinal perfusates of rats pretreated with Delta(9)-THC, CP55,940 or AEA. The supernatant was lyophilized and the concentrations of dynorphin B were measured via radioimmunoassay. At a peak time of antinociception (10 min), CP55,940 and Delta(9)-THC induced significant two-fold increases in the release of dynorphin B. AEA did not significantly release dynorphin B. Upon a 30-min pretreatment with the drugs, no significant dynorphin B release was observed, although antinociceptive effects persisted for CP55,940 and Delta(9)-THC. Previous work indicates that Delta(9)-THC releases dynorphin A while AEA releases no dynorphin A. This study confirms that although all three test drugs produced significant antinociception at 10 min, the endocannabinoid, AEA, does not induce antinociception via dynorphin release. Thus, our data indicate a distinct mechanism which underlies AEA-induced antinociception.

A comparison between microwave irradiation and decapitation: basal levels of dynorphin and enkephalin and the effect of chronic morphine treatment on dynorphin peptides.

Opioid peptides were analysed in tissue extracts of various brain structures and the pituitary gland from rats sacrificed by microwave irradiation, and compared with peptide levels in tissue extracts from decapitated rats. Dynorphin A, dynorphin B and Leu-enkephalinArg6, derived from prodynorphin, and Met-enkephalinArg6Phe7 from proenkephalin, were measured. Basal immunoreactive levels of dynorphin A and B were consistently higher in extracts from microwave-irradiated rats, whereas in these extracts immunoreactive levels of Leu-enkephalinArg6, an endogenous metabolite of dynorphin peptides, were either lower than, the same as or higher than in decapitated rats. Immunoreactive levels of Met-enkephalinArg6Phe7 were higher in microwave-irradiated rats. Effects of morphine treatment on prodynorphin peptide levels were evaluated and compared with previous findings in decapitated rats. Dynorphin immunoreactive levels were higher in the nucleus accumbens and striatum of morphine-tolerant rats than in corresponding areas in saline-treated rats. These results indicate tissue-specific metabolism of prodynorphin peptides and show that metabolism of opioid peptides occurs during the dissection procedure after decapitation of the rat even though precautions are taken to minimize degradation.

Role of endogenous opioids and catecholamines in vasovagal syncope.

Head-up tilt testing demonstrates vasovagal mechanisms as a cause for syncope, but the pathophysiology underlying this condition remains unclear. The aim of this study was (i) to measure plasma beta-endorphins, adrenocorticotrophic hormone, cortisol, catecholamines, and brain natriuretic peptide during head-up tilt, and (ii) to assess the effect of naloxone infusion during head-up tilt in subjects with reproducible vasovagal syncope. During the assessment of unexplained syncope, 71 subjects underwent a total of 93 tilt tests (60-70 degrees head upwards for 40-45 min or until syncope occurred) during which frequent blood sampling was performed. Subjects with a positive tilt test (n = 56) (mean duration to syncope 23.6 min) showed a larger rise in beta-endorphin levels prior to syncope (baseline 4.7 +/- 2.2 vs syncope onset 6.9 +/- 3.2 pmol.l-1, P = 0.0001) than those with a negative test (n = 37) (baseline 3.9 +/- 3.9 vs end of test 4.9 +/- 2.3 pmol.l-1, P = 0.03). During tilting, adrenocorticotrophic hormone, cortisol, and noradrenaline increased; adrenaline and brain natriuretic peptide remained unchanged; and these responses were similar in positive and negative test groups. Naloxone (2.6 mg.kg-1 i.v. bolus followed by 20 micrograms.kg-1.min-1 infusion), administered in a double-blind fashion during head-up tilt in nine subjects, failed to modify either the time to syncope or the vasodepressor response. Thus, endogenous opioids appear not to be an important trigger for vasovagal syncope, and other pathophysiological mechanisms should be considered.

Effects of ACTH 1-24 on hydrolysis of beta-casomorphin-4-nitroanilide in brain homogenates in vivo and in vitro.

Administration of ACTH 1-24 to 3-10 days old rats produced a significant decrease in hydrolysis of beta-casomorphin-4-nitroanilide (beta-CM-4NA) in the cytosolic fraction of brain homogenate in the first three hours after injection. Corticosterone treatment did not modify the hydrolysis of the substrate. ACTH 1-24 but not ACTH 4-10, Met-enkephalin or Leuenkephalin given to the brain homogenate resulted in a dose-dependent decrease in liberation of 4NA from beta-CM-4NA. Kinetic data suggest competitive inhibition of ACTH molecule on hydrolysis of beta-CMA-4NA. The ACTH treatment, however, did not influence the hydrolysis of Pro-Gly-4NA or Pro-Pro-4NA in the brain homogenate in vitro.

The biologic basis of posttraumatic stress.

The psychological effects of trauma are accompanied by biologic changes in the stress response that persist when people develop posttraumatic stress disorder (PTSD). This article explores the nature of this altered stress response; provides a review of the symptomatology of PTSD; describes how developmental level affects the biology of the trauma response, the stress response, and the psychobiology of PTSD; and discusses the implications for psychopharmacologic treatment.

Lead toxicity and alterations in opioid systems.

The opioid peptide system in the brain is probably the most extensive and diverse peptidergic transmission system. Three peptide precursors, pro-opiomelanocortin, proenkephalin and prodynorphin produce over 20 opioid peptides collectively known as the endorphins, enkephalins and dynorphins. Their effects are mediated by three receptors mu, delta and kappa, and the opioid system has control over several physiological functions including pain, locomotion, mood, diuresis, thermoregulation, stress, respiratory, gastrointestinal and cardiovascular function. Lead treatment (primarily using rat models) has shown that exposure to this metal in the perinatal period alters the development of endorphins and enkephalins, toxic effects which for the pro-opiomelanocortin products may be manifested at the gene level. Lead also alters the development of mu and delta receptors and biological responses to opioids such as analgesia, locomotion and stress responses. There are indications that the dynorphin/kappa opioid system is less affected than the mu and delta systems and this may suggest vulnerability to toxicity in the postnatal period as kappa systems are fully developed at birth whilst mu and delta systems are immature. In addition, hypothalamic and pituitary disruption of opioid peptides, plus alteration of stress-mediated activity by lead point to toxicity upon opioid controlled hormonal function. Comparative studies with other CNS neurochemicals and measures of blood lead levels suggest that opioid peptides are among the most sensitive neurotransmitter/neurohormonal systems to toxic insult by lead.

Calcitonin nasal spray reduces opioid withdrawal syndrome without modification of endogenous opioid secretion.

It has been suggested that the well known analgesic effect of calcitonin (CT) may result from an enhanced secretion of opioid peptides. The purpose of this double-blind, controlled study was therefore to evaluate the effectiveness of CT on the opiate withdrawal syndrome. 20 drug addicts were randomly allocated to receive either 200 UI/day of salmon CT (n = 10) or placebo (n = 10) by nasal spray, after the abrupt withdrawal of low-dose methadone (20 mg/day). The severity of the withdrawal syndrome was evaluated by means of a score derived from a symptom check-list. Plasma beta-endorphin, glucose and insulin levels were measured before and after CT administration. The subjects treated with spray CT had significantly lower score than those treated with placebo. Beta-endorphin levels did not show any significant variation in both groups. An inhibitory action of CT on insulin secretion was observed. Our data suggested that CT might be considered a useful supportive measure for opiate withdrawal. CT action does not seem to involve the opioid system, but is probably mediated by a direct action on specific receptors or by a modulation of noradrenergic pathways.

[The role of opioids in mediating the antinociceptive influences of hypothalamic "pleasure zones"]. / Rol' opioidov v oposredovanii antinotsitspetivnykh vliianii gipotalamicheskikh "zon nagrady".

In 41-60-day old rabbits, the antinociceptive effect of stimulation of the hypothalamic "rewarding areas" was estimated by a decrease in the EPs' amplitude as recorded in the thalamus' parafascicular complex in response to nociceptive stimulation of a hind-limb. The EPs were inhibited at a certain power of the current stimulating the "rewarding areas" in all the animals. In complete inhibition of nociceptive EPs, low doses of naloxone weakened it in 4 rabbits out of 6, whereas high doses only weakened it in 1 animal out of 4. In incomplete inhibition of the EPs, low doses of naloxone enhanced the antinociceptive effect up to complete suppression of EPs in 3 cases out of 6, whereas high doses did not affect this effect in 5 cases out of 7. Neurochemical mechanisms of the EPs inhibition in unspecific nociceptive complex of the thalamus during stimulation of hypothalamic "rewarding areas", are discussed.

Effects of captopril on opioid peptides during exercise and quality of life in normal subjects.

In a placebo-controlled, randomized, crossover, double-blind study of 17 normal volunteers, we examined the effects of captopril on the concentration of opioid peptides during bicycle exercise and on quality of life after a 2-week treatment period. Two exercise tests (progressive exercise and constant work rate exercise) were performed. Maximum oxygen uptake and blood lactate concentrations were measured in progressive exercise tests. The exercise intensities corresponding to a 1/2 lactate threshold, a lactate threshold, and a 4 mmol/L lactate concentration were determined. Constant work rate exercise at selected work loads for 20 minutes was carried out to measure the concentrations of opioid peptides and other hormones. Quality of life was assessed after the 2-week treatment period. Captopril treatment had no effect on the exercise response of blood pressure, heart rate, maximum VO2, and maximum work loads. The plasma concentrations of lactate, epinephrine, norepinephrine, and aldosterone increased during exercise and captopril did not change them. Beta-endorphin levels and plasma renin activity also increased during exercise, and the increases were greater with captopril treatment. Met-enkephalin and leu-enkephalin concentrations did not increase during exercise. According to responses in the quality of life questionnaires, administration of captopril improved the physiologic state more than the placebo did. These findings suggest that captopril may act on the central nervous system involving an increase in the beta-endorphin level.

[The biochemical antagonism of cholinolytics and cholinomimetics at the level of the opiate system]. / Biokhimicheskii antagonizm kholinolitikov i kholinomimetikov na urovne opiatnoi sistemy.

The experiments on albino rats with the use of the radioimmunoassay showed that M-cholinoblockers (atropine, amizil, glypine) decrease the contents of enkephalins and beta-endorphin in the brain and blood whereas M-cholinomimetics (arecoline, nicotine, physostigmine) increase the level of opioid neuropeptides. This suggested that between cholinoblockers and cholinomimetics there is not only functional but also biochemical antagonism at the level of the opiate system. In addition, the statement is developed that toxic effects of cholinoblockers and cholinomimetics are largely related to disturbances of metabolism and function of opioid neuropeptides.

[The endorphins of the epithelial and subepithelial structures of the rat small intestine and the evolutionary hypotheses of the formation of the mechanisms of the negative regulation of their synthesis]. / Endorfiny épitelial'nykh i subépitelial'nykh struktur tonkogo kishechnika krys i nekotorye évoliutsionnye gipotezy formirovaniia mekhanizmov negativnoi reguliatsii ikh sinteza.

The effects of the agonist of the glucocorticoid hormones dexamethasone and dopamine antagonist--haloperidol on the concentration of immunoreactive alpha-, beta- and gamma-endorphins in duodenum, ileum, and jejunum of rats were studied. Besides the extracts of the intestines, the immunoreactive endorphins were measured in the extracts of their mucosa-submucosa and muscle-serous layers, that allowed to separate the endorphin-producing cells of the nervous system (muscle-serous layer) from endorphin producing cells of endocrine and immune systems (mucosa-submucosa layer). The injection of dexamethasone (0.2 mg per rat, daily for 6 days) caused the reliable decrease in concentrations of all three types of endorphins in mucosa-submucosa and muscle-serous layer of duodenum, ileum, and jejunum. Under the action of haloperidol (0.6 mg per rat, daily for 6 days) the reliable increase of beta-endorphin concentration was noticed only in jejunum. The suggestion is made that two distinct subpopulations of endorphin-producing cells exist in the intestine: in one cells endorphin synthesis is regulated by glucocorticoids, as in the anterior lobe of pituitary, in the other cells the synthesis of endorphins is regulated by dopamine, as in the cells of the intermediate lobe of pituitary. It is suggested that both glucocorticoid and dopamine types of regulation of endorphins synthesis were formed in the intestine or even in the gastric cavity. In process of evolution the cells with glucocorticoid type of regulation gave rise to the anterior lobe of pituitary, the cells with the dopamine type of regulation--to the intermediate lobe.

Diltiazem and verapamil lower blood pressure in the unanaesthetized rat through CNS mechanisms involving endogenous opioids.

1. To evaluate and compare the effects of the calcium channel blockers, diltiazem and verapamil, on CNS modulation of blood pressure, unanaesthetized and unrestrained rats with catheters previously inserted into the lateral cerebral ventricle and femoral artery received intracerebroventricular (i.c.v.) administration of diltiazem or verapamil, 10 or 50 micrograms/kg, or their diluent. 2. Diltiazem, at both 10 and 50 micrograms/kg i.c.v., produced significant (P less than 0.05) decreases in systolic and diastolic blood pressure and heart rate. Verapamil, at 50 micrograms/kg but not at 10 micrograms/kg i.c.v., produced a significant (P less than 0.05) decrease in blood pressure, while both doses significantly (P less than 0.05) decreased heart rate. 3. To examine the endogenous opioid systems as potential modulators of the effects of these calcium antagonists, the mu opioid antagonist naloxone, 20 micrograms/kg, was administered i.c.v. either before or after each calcium antagonist. Naloxone reversed and prevented the reduction in blood pressure produced by both agents. The decrease in heart rate produced by verapamil but not diltiazem was reversed by naloxone. 4. The results suggest that: (1) calcium channels in neuron membranes in the CNS play a role in blood pressure regulation; (2) at least part of the blood pressure reduction produced by calcium blockers may be effected in the CNS; and (3) central opioid mechanisms modulate part of the action of the calcium antagonists verapamil and diltiazem on blood pressure.

The effect of single and repeated ethanol administration of hypothalamic opioid systems activity --an in vitro release study.

The effect of ethanol administration on the in vitro release of alpha-neoendorphin (ANEO) and Met-enkephalin-Arg6-Gly7-Leu8 (MEAGL), peptides derived from prodynorphin and proenkephalin, respectively, was studied in the rat hypothalamus. Single ethanol administration had no effect on the tissue level and potassium-stimulated release of these peptides. Repeated ethanol administration increased the release of ANEO and reduced the release of MEAGL from hypothalamic slices. Two days after cessation of ethanol administration the release of MEAGL returned to control values, whereas the release of ANEO was significantly inhibited. On the other hand, the tissue level of those peptides remained unchanged after repeated ethanol or 2 days after its last administration. The present study shows that repeated treatment with ethanol may lead to an increase in the prodynorphin neurons' sensitivity to the depolarizing effect of potassium. In contrast, the sensitivity of the proenkephalin system to ethanol seems to be inhibited. Thus, ethanol appears to have an opposite effect on the sensitivity of hypothalamic proenkephalin and prodynorphin neurons.

Interaction of diazepam and naloxone on acupuncture induced pain relief.

We have studied if 2 Hz electroacupuncture alleviates chronic nociceptive pain and if so whether the alleviation was related to the release of endogenous opioids. Thirty-two patients suffering from osteoarthritis were subjected to electroacupuncture, with or without pretreatment with naloxone or diazepam. The effect of the different experimental procedures was assessed using scales for the intensity (sensory component) and unpleasantness (affective component) of pain. Electroacupuncture induced a significant alleviation of pain. This alleviation was more significant on the affective scales (p less than 0.01) than on the sensory scales (p less than 0.05). After pretreatment with diazepam or naloxone, the subsequent pain alleviating effect was reduced. These data indicate that acupuncture induced analgesia may partly be mediated through endogenous opioids which are affected by pretreatment with diazepam or naloxone.