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Background: Following the hypothesis that blocking opioid receptors leads to a decline in opiate-modulated dissociative phenomena, experiences with naltrexone as medication for dissociative symptoms have been gained since 1999 (mainly in doses of 25-100 mg/day). Patients and methods: In this study patients with severe trauma-related and dissociative disorders were treated with naltrexone in doses of 2-6 mg/day (0.06 mg/kg body weight). Results: The low dose treatment with naltrexone proved to be effective whereby 11 out of 15 patients reported immediate positive effects and 7 described a lasting helpful effect. The majority of patients who felt positive effects reported a clearer perception of both their surroundings and their inner life. Assessment of reality and dealing with it improved as did the perception of their own body and affects as well as self-regulation. The treatment was very low in side effects. Conclusion: Treatment with low-dose naltrexone may be a helpful element in the treatment of patients with complex posttraumatic stress disorder. However, it has to be realized that the decrease of dissociation may lead patients to a not yet resolvable challenge, in as much as dissociation had previously been a necessary mechanism of self-protection. [ABSTRACT FROM AUTHOR]

Abstract: This review gives an overview of those in vivo imaging studies on synaptic neurotransmission, which so far have been performed on patients with movement disorders and/or dementia. Thereby, the focus is on disease-related deficiencies within the functional entity of the dopaminergic, serotonergic, cholinergic, glutamatergic, GABAergic or opioid synapse. In vivo investigations have yielded highly consistent results on the dysfunction of synaptic constituents in the majority of diseases covered by this overview. Findings show presynaptic dysfunctions in idiopathic as well as early-onset Parkinson''s disease with decreases in striatal dopamine synthesis (57 out of a total of 59 reports on both types of Parkinson''s disease), storage (nine out of nine reports), release (two out of three reports) and transporter binding (95 out of 95 reports). In contrast, the “Parkinson plus” syndromes multiple system atrophy and progressive supranuclear palsy are characterized by both pre- and postsynaptic deficiencies with reductions in striatal dopamine synthesis (11 out of a total of 11 reports on both types of “Parkinson plus” syndromes), storage (four of four reports), and transporter binding (27 out of 27 reports) as well as D1 (two out of two reports) and D2 receptor binding (34 out of 36 reports). This does not hold for the “Parkinson plus” syndromes dementia with Lewy bodies and corticobasal degeneration. For these diseases, for the time being, firm evidence of alterations in D1 and/or D2 receptor binding is lacking. In patients with Huntington''s disease, mainly postsynaptic dysfunctions with reductions of striatal D1 (six out of six reports) and D2 receptor binding (15 out of 15 reports) were observed. Alzheimer''s disease is characterized by both pre-and postsynatic deficiences of the cholinergic system with decreases of cortical acetylcholine storage (one out of two reports) and both musarinic (seven out of 10 reports) and nicotinic cholinergic receptor binding (three out of six reports). Moreover, reductions in cortical (one out of three reports) and limbic 5-HT1A (three out of three reports) and cortical (four out of four reports) and limbic 5-HT2A receptor binding (one out of two reports) were observed. Moreover, there is evidence for a cortical (four out of six reports) and cingulate (three out of three reports) increase of peripheral benzodiazepine receptor binding indicative of microglial activation. In the majority of investigations on patients with Alzheimer''s disease, no alterations of presynaptic dopamine function were found, whereas all other forms of dementia including corticobasal degeneration, dementia with Lewy bodies, Parkinson''s disease dementia and frontotemporal dementia were characterized by presynatic dopaminergic deficiencies with reductions in striatal dopamine synthesis (10 out of a total of 10 reports on these types of dementia), storage (four out of four reports) and transporter binding (29 out of 29 reports). Taken together, in vivo imaging methods can be employed for the diagnosis of idiopathic and early-onset Parkinson''s disease as well as “Parkinson plus” syndromes and Huntington''s disease. Moreover, differentiation is feasible between, firstly, Parkinson''s disease and the “Parkinson plus” syndromes multiple system atrophy and progressive supranuclear palsy, secondly, multiple system atrophy/progressive supranuclear palsy and the other “Parkinson plus” syndromes dementia with Lewy bodies and corticobasal degeneration, and, thirdly, Alzheimer''s disease and other forms of dementia. [Copyright &y& Elsevier]

Abstract: In vivo exposure has become the gold standard treatment for specific phobia. The endogenous opioid system is one mechanism proposed to explain why exposure provides such quick and effective treatment for specific phobia. The effect of naltrexone on fear and avoidance behavior was investigated among 15 specific phobia participants who received exposure treatment. Participants were randomly assigned to receive naltrexone, placebo, or no drug prior to attending one-session exposure treatment. Mixed effects regression results revealed that across time, the naltrexone group tolerated significantly less time in the room with the feared animal (Behavioral Avoidance Index) as compared to the placebo and no drug groups. Phobic individuals assigned to the naltrexone group had significantly higher fear ratings across time in comparison to the placebo group. Results provide support for the endogenous opioid system as a potential underlying biological mechanism associated with behavioral changes during in vivo exposure. [Copyright &y& Elsevier]

Objective: Evaluation of the effects of naltrexone on hyperinsulinemia and hyperandrogenemia in hyperandrogenemic, hyperinsulinemic women. Design: Controlled clinical study. Setting: Department of Gynecologic Endocrinology and Reproductive Medicine, Center of Obstetrics and Gynecology, Medical University of Innsbruck, Austria. Patient(s): Thirty-nine hyperandrogenemic, hyperinsulinemic women were studied. Intervention(s): Women were treated with naltrexone (50 mg/d) for ≥3 weeks. Main Outcome Measure(s): Body mass index (BMI), gonadotropin (LH, FSH) and androgen (T, free T, DHEAS) levels, and plasma levels of glucose, insulin, and C-peptide, during a standard 75-g oral glucose tolerance test (OGTT), were determined before and during chronic opiate receptor blockade. Result(s): The BMI did not change during therapy. When OGTT was repeated after treatment with naltrexone, glucose levels were not different from those before treatment. Insulin response, however, had dramatically declined. We also observed a significant decrease in the levels of serum androgens. Conclusion(s): Hyperinsulinemia associated with hyperandrogenemia can be improved or completely abolished by chronic opiate receptor blockade. This observation suggests that endogenous opiates play a critical role in the process leading to hyperinsulinemia in hyperandrogenemia. [Copyright &y& Elsevier]

Abstract: This double blind, placebo-controlled study examined the effects of an opiate antagonist, naltrexone, on nociceptive flexion reflex (NFR) thresholds and subjective pain in individuals with and without a parental history of hypertension. Using a repeated measures design, NFR threshold was repeatedly assessed on two testing days after administration of either placebo or naltrexone. Immediately after NFR threshold was determined, participants rated the level of pain experienced during the preceding NFR assessment, and at the end of each session participants’ electrocutaneous pain threshold was assessed. Two primary findings were obtained. First, individuals with a parental history of hypertension exhibited attenuated pain sensitivity. Second, endogenous opioid blockade was associated with increased pain ratings in women but with increased pain threshold in men. In sum, the present study did not support a direct involvement of the endogenous opioid system in the attenuated pain sensitivity observed in individuals at increased risk for hypertension. [Copyright &y& Elsevier]

Abstract: This paper is the 26th consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2003 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular–biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). [Copyright &y& Elsevier]

This paper is the twenty-fifth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2002 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17). [Copyright &y& Elsevier]

High CO2-sensitivity, one of the major characteristics of the cerebrovascular bed, has been shown to be influenced by a variety of factors. There are no reports, however, on the involvement of the endogenous opioid peptides in the modulation of the CO2-sensitivity of the cerebral and spinal cord vessels, either in normotensive or, in hypotensive conditions. The effect of general opiate receptor blockade (1.0 mg/kg naloxone, i.v.) on regional cerebrovascular CO2-sensitivity was studied with radiolabeled microspheres in 10 distinct brain and spinal cord regions of the anesthetized cat. The CO2-induced flow changes were investigated in normotensive, in moderately hypotensive (MAP=80 mmHg) and in deep hypotensive cats (MAP=40 mmHg). The systemic arterial pressure was lowered by hemorrhage. In the normotensive cats, opiate receptor blockade caused no changes in the vascular CO2-sensitivity in the investigated cerebral and spinal cord regions. In moderate hypotension, cerebral and spinal CO2-sensitivity was significantly reduced by the hemorrhage itself, but remained unaffected by the naloxone administration. In deep hemorrhagic hypotension, however, general opiate receptor blockade resulted not only in a further reduction of the already impaired CO2-sensitivity, but even in a reversal of the effect of CO2 from flow increase to flow decrease. These results indicate that endogenous opioid peptides, which do not seem to influence cerebrovascular reactions in steady-state, normotensive conditions, may contribute significantly to the maintenance of the normal vasodilatory response of the cerebral and spinal cord vessels to CO2 during hemorrhage-induced deep arterial hypotension. [Copyright &y& Elsevier]

This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular–biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (), and the roles of these opioid peptides and receptors in pain and analgesia (); stress and social status (); tolerance and dependence (); learning and memory (); eating and drinking (); alcohol and drugs of abuse (); sexual activity and hormones, pregnancy, development and endocrinology(); mental illness and mood (); seizures and neurologic disorders (); electrical-related activity and neurophysiology (); general activity and locomotion (); gastrointestinal, renal and hepatic functions (); cardiovascular responses (); respiration and thermoregulation (); and immunological responses (). [Copyright &y& Elsevier]

AbstractRats exposed to a low‐light, low‐noise, novel environment exhibit differences in individual locomotor response to the novelty stressor. The categorization of rats in a locomotor screening procedure as low‐ (LR) or high‐responders (HR), where LRs are in the low locomotor range while HRs belong to the high locomotor range, is significant in that HRs show higher activity in mesencephalic dopaminergic projection neurons, and also show a higher propensity to self‐administer psychostimulants and other drugs of abuse compared with LRs. In this study, we examined the neurobiological basis of dopaminergic hyperactivity by comparing in HRs and LRs the steady‐state differences in regulatory inputs to mesencephalic (substantia nigra and ventral tegmental area: VTA) dopaminergic neurons. In particular, using in situ hybridization, we studied levels of mRNA for tyrosine hydroxylase (TH) and cholecystokinin (CCK) in the mesencephalon, and for preprodynorphin (DYN), preproenkephalin (PPE), and preprotachykinin (PPT) in the striatum and nucleus accumbens (Acb). We also evaluated TH levels by radioimmunocytochemistry (TH‐RIC) in striatal, accumbal and mesencephalic regions. HRs versus LRs had lower levels of neurochemicals belonging to the intrinsic inhibitory input to dopaminergic neurons in the VTA, e.g. lower TH‐RIC (–25%) and CCK‐mRNA (–48%). In contrast, HRs showed higher levels of parameters belonging to extrinsic facilitating inputs, e.g. higher PPE‐mRNA (+ 37%). In addition, HRs had higher DYN‐mRNA in Acb (+ 61%), which has been shown to be positively correlated with higher dopaminergic activity. These results enhance our knowledge of the neurobiological correlates of individual rats' propensities to develop drug‐intake and provide some putative mechanisms for the dopaminergic hyperactivity that characterizes drug‐prone animals. [ABSTRACT FROM AUTHOR]

Self-injuring behavior is among the most unmanageable. expensive, destructive, and unpredictable behaviors exhibited by human beings. lnterventions that Included punishment or restraint were among' the most successful for acute control of SIB. Both painful shock and restraint stimulate release of the body's own opiates Into, the bloodstream. These powerful agent, which possess analgesic and addictive properties, are more potent than morphine. Based on these observations, two versions of the opiate hypothesis have evolved to explain SIB. The analgesia hypothesis suggests that high-circulating levels of β-endorphin (βE) in individuals with SIB reduces the perception of pain. With the experience of pain reduced, individuals inflict self-harm as a form of stimulation. The addiction hypothesis presumes that the release of opiates after pain or SIB produces pleasure. As a consequence, individuals exhibiting SIB become addicted to their own opiate system. The strongest link between SIB and the opiate hypotheses is the finding that opiate receptor blockers attenuate and sometimes eliminate this behavior. In addition to providing a possible treatment for some SIB individuals, these findings suggest that a specific opiate system, βE and mu receptor, is disregulated (by elevated levels of opiates, abnormally sensitive opiate receptors, or uncoupling of co-released peptides). Recent studies have found that βE was elevated after an SIB episode, but that co-released peptides such as ACTH were not Selective release of βE after SIB provides evidence that endogenous opiates have a direct association with SIB. This association supports speculation that endogenous opiates maintain SIB. [ABSTRACT FROM AUTHOR]

The aim of this study is to analyze further the opioid receptor subtypes involved in the augmentation of behavioral activity after dopamine depletion in the nucleus accumbens of rats. Initially, the opioid receptors involved in the augmentation of locomotion produced by endogenous opioids were evaluated by microinjection of kelatorphan, an inhibitor of proteolytic enzymes that inactivates enkephalin, with or without specific antagonists for μ or δ-opioid receptors, naloxonazine or naltrindole, respectively. Kelatorphan produced a dose-dependent increase in horizontal photocell counts and vertical movements. At all doses examined the behavioral response was augmented in rats sustaining accumbal dopamine lesions. The augmentation in dopamine-depleted rats was partially blocked by naloxonazine or naltrindole. Since the motor stimulant response to intra-accumbens microinjection of the δ-opioid agonist, [ d-penicillamine]-enkephalin, was not augmented in a previous study, we tested the behavioral response to a new endogenous δ-opioid agonist, [ d-Ala] deltorphin I. The locomotor response to deltorphin was slightly augmented in dopamine-depleted rats. These data suggest that the augmentation in the motor response elicited by endogenous opioids after dopamine lesions in the nucleus accumbens involves both μ and δ-opioid receptors. [ABSTRACT FROM AUTHOR]

The participation of endogenous opiate systems in the induction and expression of learned helplessness (LH) and stress-induced analgesia (SIA) was investigated in rats exposed to escapable and inescapable footshock. Following an initial footshock, analgesia was observed only in those animals that could not control their stress exposure and this SIA was prevented by the administration of naloxone. Analgesia was no longer evident in this inescapable group after 48 h. However, exposure to a shuttlebox escape task at this time reinstated the SIA but did not produce SIA in animals previously exposed to escapable footshock. Shuttlebox escape deficits indicative of LH were also exhibited by animals that received an inescapable footshock stress 48 h prior to testing. The analgesia and LH observed in the inescapable group were not affected by the administration of naloxone (3 mg/kg, IP) 10 min before shuttlebox exposure but were prevented when the same dose of naloxone was given before the initial stress. Thus, endogenous opiates clearly participate in the initial induction of LH and SIA and, although the degree of endogenous opiate involvement in the subsequent expression of these behaviors is unclear, it seems evident that their expression can occur in the presence of opiate antagonism and may therefore require the participation of additional transmitter systems. [ABSTRACT FROM AUTHOR]

The tail-flick procedure was used to study the antinociceptive effects of physostigmine in adrenalectomized and sham-operated rats. At 5 days after surgery, they were tested 30 min after either 0.32 or 0.45 mg/kg IP physostigmine. Adrenalectomized animals showed significantly greater elevation of TF scores from predrug latencies than the sham controls at both doses of physostigmine. Following 3 days of dexamethasone replacement therapy on days 18, 19, and 20 post-surgery the antinociceptive effects of physostigmine were uniformly attenuated across doses or surgical groups. On the other hand, animals receiving saline injection instead of dexamethasone did not manifest any reduction of the physostigmine antinociceptive effect. The potentiation by adrenalectomy and the reduction following dexamethasone of the antinociceptive effects of physostigmine suggest that these effects may be mediated through hypothalamic-pituitary-adrenal mechanisms and are consistent with β-endorphin-induced sensitization of opiate or cholinergic receptors. [ABSTRACT FROM AUTHOR]

The endogenous opiate peptide, beta-endorphin (0.4, 1.0, 2.0, and 10.0 μg/kg) was injected IP into rats immediately after training in a shuttle avoidance task, and its effect on memory retention was evaluated in test sessions carried out 24 h later. The drug was found to cause retrograde amnesia, the ED being 1.0 μg/kg. Beta-endorphin immunoreactivity was measured in the hypothalamus and rest of the brain of rats submitted to training, or test sessions of shuttle avoidance learning, pseudoconditioning in the shuttle-box, tones alone, or foot-shocks alone. After training in any of the four paradigms, there was a marked (46-60%) depletion of beta-endorphin immunoreactivity in the rest of the brain. No changes were detected in the hypothalamus or after test sessions. The loss of beta-endorphin immunoreactivity may be attributed to release of this substance caused by the stimuli used for training. From the present findings, as well as previous observations on the memory-facilitating influence of the opiate receptor antagonist, naloxone, it is concluded that there is a physiological amnesic mechanism mediated by beta-endorphin (and perhaps other opoid peptides as well), which is triggered by the non-associative factors present in the various forms of learning. [ABSTRACT FROM AUTHOR]

Naloxone impairs acquisition of shuttle avoidance behavior (0.8 mg/kg IP) and habituation to a rearing response to a tone (1.6 mg/kg IP) in rats. β-Endorphin (2 μg/kg IP) has no effect on acquisition, but, when given prior to test sessions, facilitates retrieval of the two tasks. Naloxone has no effect of its own upon retrieval. In addition to these effects, the pretraining administration of β-endorphin disrupts, and that of naloxone facilitates retention of the two tasks. The results are consistent with the hypothesis that these two forms of learning are state-dependent on the release of β-endorphin (and, perpaps, of other opiate peptides as well), that this substance is released during training in a sufficient amount for this purpose, and that, in addition, there is a physiological amnesic mechanism mediated by opiate peptides. Furthermore, the results are also consistent with previous observations that β-endorphin is released from the rat brain during training, but not during test sessions of the two tasks (Izquierdo et al., 1980b). The possibility is discussed that state-dependency and the amnesic effect comprise one single, rather than two separate mechanisms. [ABSTRACT FROM AUTHOR]

The post-training IP administration of naloxone (0.8 mg/kg) facilitates memory consolidation of the habituation of a rearing response to a tone in rats. Amphetamine (1.0-2.5 mg/kg or nicotine (0.2-0.5 mg/kg), and amphetamine (2.5 mg/kg) plus nicotine (0.5 mg/kg) have no effect. The higher doses of amphetamine or nicotine, however, when given together with a dose of naloxone which is ineffective alone (0.2 mg/kg), markedly enhance consolidation. Haloperidol (0.5 mg/kg), propranolol (0.5 mg/kg), and phenoxybenzamine (2.0 mg/kg) have no effect on their own; whereas tolazoline (2.0 mg/kg) impairs consolidation. The effect of naloxone (0.8 mg/kg) is antagonized by haloperidol and by propranolol, but not by phenoxybenzamine or tolazoline. The results suggest that naloxone causes memory facilitation through the release of central dopaminergic and beta-adrenergic mechanisms from a tonic inhibitory influence of endogenous opiate peptide systems. [ABSTRACT FROM AUTHOR]

We review three possible theoretical mechanisms for the placebo effect: conditioning, expectancy and endogenous opiates and consider the implications of the first two for clinical research and practice in the area of pain management. Methodological issues in the use of placebos as controls are discussed and include subtractive versus additive expectancy effects, no treatment controls, active placebo controls, the balanced placebo design, between- versus within-group designs, triple blind methodology and the double expectancy design. Therapeutically, the possibility of shaping negative placebo responses through placebo sag, overservicing and the use of placebos on their own are explored. Suggestions for using conditioned placebos strategically in conjunction with nonplacebos are made and ways of maximizing the placebo component of nonplacebo treatments are examined. Finally, the importance of investigating the placebo effect in its own right is advocated in order to better understand the long-neglected psychological aspects of the therapeutic transaction. [ABSTRACT FROM AUTHOR]

Pain, the most common symptom reported among patients in the primary care setting, is complex to manage. Opioids are among the most potent analgesics agents for managing pain. Since the mid-1990s, the number of opioid prescriptions for the management of chronic non-cancer pain (CNCP) has increased by more than 400%, and this increased availability has significantly contributed to opioid diversion, overdose, tolerance, dependence, and addiction. Despite the questionable effectiveness of opioids in managing CNCP and their high rates of side effects, the absence of available alternative medications and their clinical limitations and slower onset of action has led to an overreliance on opioids. Conolidine is an indole alkaloid derived from the bark of the tropical flowering shrub Tabernaemontana divaricate used in traditional Chinese, Ayurvedic, and Thai medicine. Conolidine could represent the beginning of a new era of chronic pain management. It is now being investigated for its effects on the atypical chemokine receptor (ACK3). In a rat model, it was found that a competitor molecule binding to ACKR3 resulted in inhibition of ACKR3's inhibitory activity, causing an overall increase in opiate receptor activity. Although the identification of conolidine as a potential novel analgesic agent provides an additional avenue to address the opioid crisis and manage CNCP, further studies are necessary to understand its mechanism of action and utility and efficacy in managing CNCP., Competing Interests: Conflict of Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021, Author(s).)

A peptide material with opiate-like activity in the guinea-pig ileum was extracted from porcine pituitaries using a hot glacial acetic acid extraction method and was partially purified by gel filtration. When injected intraventricularly in rats, these purified peptides induced strong analgesia, catalepsy, respiratory depression and other opiate-like effects, which lasted for several hours. [ABSTRACT FROM AUTHOR]