Endogenous Opioid System Research Articles

Buprenorphine as a Treatment for Major Depression and Opioid Use Disorder.

Rates of major depressive disorder (MDD) are disproportionally high in subjects with opioid use disorder (OUD) relative to the general population. MDD is often more severe in OUD patients, leading to compliance issues with maintenance therapies and poor outcomes. A growing body of literature suggests that endogenous opioid system dysregulation may play a role in the emergence of MDD. Buprenorphine, a mixed opioid receptor agonist/antagonist approved for the treatment of OUD and chronic pain, may have potential as a novel therapeutic for MDD, especially for patients with a dual diagnosis of MDD and OUD. This paper presents a comprehensive review of papers relevant to the assessment of buprenorphine as a treatment for MDD, OUD, and/or suicide compiled using electronic databases per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The principal goal of this literature review was to compile the clinical studies that have interrogated the antidepressant activity of buprenorphine in opioid naïve MDD patients and OUD patients with comorbid MDD. Evidence supporting buprenorphine's superiority over methadone for treating comorbid OUD and MDD was also considered. Finally, recent evidence for the ability of buprenorphine to alleviate suicidal ideation in both opioid-naïve patients and opioid-experienced patients was evaluated. Synthesizing all of this information, buprenorphine emerges as a potentially effective therapeutic for the dual purposes of treating MDD and OUD.

Pregestational oxycodone exposure does not impact future maternal care or drug preference in the postpartum mouse.

Females are uniquely sensitive to drugs of abuse at specific points in their reproductive cycle. Females' endogenous opioid system contributes to both reward-related processes and maternally relevant physiological functions, yet less is known about how adolescent opioid exposure impacts females' future behavior, ranging from parental caregiving to opioid preference. The present study explores 2 questions: (a) are there sex differences in response to adolescent oxycodone exposure, spontaneous withdrawal, and oxycodone preference in adulthood, and (b) to what extent does this pregestational opioid exposure alter females' future maternal caregiving behavior? Female and male mice received 12d of oxycodone or saline injections during mid/late adolescence, and drug was then withheld. Some females were then mated and experienced a drug-free pregnancy. Following parturition, females' maternal behavior and motivation were assessed. All mice then underwent a place conditioning procedure to assess the incentive value of oxycodone during adulthood. Mice displayed similar behavioral responses to oxycodone (e.g., sensitization) and patterns of withdrawal behaviors, independent of sex. Mice showed strong group preferences for the oxycodone-paired chamber, and the strength of these preferences did not differ by sex or maternal status. Postpartum females' maternal behavior and motivation were also similar despite adolescent drug history. Together, results did not suggest overt sex differences in response to adolescent oxycodone exposure and that, in females, a range of motivated behaviors may be relatively resilient to such perturbations during adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review.

BackgroundThe mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first, to our knowledge, systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders.MethodsWe systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures.ResultsWe found 12 relevant studies for depressive disorders and 4 for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine, and serotonin systems in placebo antidepressant and anxiolytic effects.ConclusionsSeveral brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

The placenta as a target of opioid drugs†.

Opioid drugs are analgesics increasingly being prescribed to control pain associated with a wide range of causes. Usage of pregnant women has dramatically increased in the past decades. Neonates born to these women are at risk for neonatal abstinence syndrome (also referred to as neonatal opioid withdrawal syndrome). Negative birth outcomes linked with maternal opioid use disorder include compromised fetal growth, premature birth, reduced birthweight, and congenital defects. Such infants require lengthier hospital stays necessitating rising health care costs, and they are at greater risk for neurobehavioral and other diseases. Thus, it is essential to understand the genesis of such disorders. As the primary communication organ between mother and conceptus, the placenta itself is susceptible to opioid effects but may be key to understanding how these drugs affect long-term offspring health and potential avenue to prevent later diseases. In this review, we will consider the evidence that placental responses are regulated through an endogenous opioid system. However, maternal consumption of opioid drugs can also bind and act through opioid receptors express by trophoblast cells of the placenta. Thus, we will also discuss the current human and rodent studies that have examined the effects of opioids on the placenta. These drugs might affect placental hormones associated with maternal recognition of pregnancy, including placental lactogens and human chorionic gonadotropin in rodents and humans, respectively. A further understanding of how such drugs affect the placenta may open up new avenues for early diagnostic and remediation approaches.

Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

µ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [11C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.

Naltrexone moderates the association of alcohol use and affect among adolescent drinkers in daily life.

Naltrexone is an efficacious medication for the treatment of alcohol use disorder in adults. As an opioid receptor antagonist, naltrexone blocks activation of the endogenous opioid system, which is involved in the affectively reinforcing properties of substance use. Few studies, however, have examined the moderating effect of naltrexone on the association between affect and alcohol use. Additionally, most existing research on naltrexone has been with adults in the human laboratory. We conducted a secondary analysis of ecological momentary assessment data from a randomized, double-blinded, placebo-controlled cross-over study that compared naltrexone (50mg/daily) and placebo in 26 adolescents (15 to 19years old) who exhibited problematic drinking patterns. Multilevel models tested whether naltrexone moderated associations of alcohol use with both positive and negative affect (PA, NA). Results indicated that, during naltrexone treatment, greater estimated blood alcohol concentration (eBAC) levels were associated with greater NA further into drinking episodes. In turn, greater NA after the first drink of an episode was associated with reduced subsequent eBAC values during naltrexone treatment. Low PA was also associated with lower subsequent eBAC levels in the naltrexone condition after the first drink. These findings support the idea that naltrexone can disrupt the association between affect and alcohol use, effects that emerge later in drinking episodes. Greater attention to the effects of naltrexone on affect and reinforcement may help to tailor psychotherapy to maximize the benefits of naltrexone. However, in the present study, as most drink reports were in the first 2h of the drinking episode and participants reported affect only at the first three end-drink reports of a drinking episode (limiting the number of drinks reported), we had reduced power to detect effects in the continuation phase. Thus, replication of the findings is needed using a design that assesses the impact of naltrexone across the entire episode.

Endogenous opioid system in the medial prefrontal cortex is involved in placebo analgesia

Endogenous opioid system in the medial prefrontal cortex is involved in placebo analgesia

Title: Novel Analgesic Potential of ß2-Agonists for Neuropathic Pain via ß2-Agonist Action.

Multimodal therapies are often employed to treat chronic pain, and ß2-agonists are a potential drug class that shows promise. The primary aim of this paper is to discuss the role of ß2-agonists as an adjunctive therapy for chronic pain based on the current literature. Recent studies in mouse models have shown that the ß2-adrenergic system plays an essential role in the analgesic properties of antidepressant drugs used to treat neuropathic pain and that the adrenergic relies on an intact endogenous opioid system to be effective. Studies also show that ß2-agonism alone is adequate to exert anti-allodynic effects in a mouse model. This paper summarized the basic physiology and pharmacology of the sympathetic nervous system and specifically the ß2-adrenergic system and summarized current literature in its involvement in the treatment of chronic neuropathic pain.

Unravelling the pathophysiology of chronic kidney disease-associated pruritus.

ABSTRACTFor decades, itch related to chronic kidney disease (CKDaP) has been a clinical problem, but the aetiology and pathophysiology of CKDaP are still not yet fully understood—currently the underlying pathophysiological mechanisms are thought to be multifactorial. As new therapeutic targets have recently been identified and clinical trials have shown promising results, our current understanding of the interrelationships has expanded significantly. Here we review the pathophysiology and recent findings on modulation and sensitization of itch contributing to the development of CKDaP, covering hypothesis regarding immune system dysfunction, metabolic changes, uremic toxin deposition, peripheral neuropathy and imbalances in the endogenous opioid system.

The inhibition of enkephalin catabolism by dual enkephalinase inhibitor: A novel possible therapeutic approach for opioid use disorders.

Despite the increasing impact of opioid use disorders on society, there is a disturbing lack of effective medications for their clinical management. An interesting innovative strategy to treat these disorders consists in the protection of endogenous opioid peptides to activate opioid receptors, avoiding the classical opioid-like side effects. Dual enkephalinase inhibitors (DENKIs) physiologically activate the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins and increasing their half-lives and physiological actions. The activation of opioid receptors by the increased enkephalin levels, and their well-demonstrated safety, suggests that DENKIs could represent a novel analgesic therapy and a possible effective treatment for acute opioid withdrawal, as well as a promising alternative to opioid substitution therapy minimizing side effects. This new pharmacological class of compounds could bring effective and safe medications avoiding the major limitations of exogenous opioids, representing a novel approach to overcome the problem of opioid use disorders. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

The Expression Pattern of Genes Related to Melanogenesis and Endogenous Opioids in Psoriasis.

The melanocortin system is a major regulator of stress responses in the skin and is responsible for the induction of melanin synthesis through activation of melanogenesis enzymes. The expression of both melanocortin system genes and melanogenesis enzyme genes is altered in psoriasis, and the focus here was on twelve genes related to the signal transduction between them. Additionally, five endogenous opioid system genes that are involved in cutaneous inflammation were examined. Quantitative real-time-PCR was utilized to measure mRNA expression in punch biopsies from lesional and non-lesional skin of psoriasis patients and from the skin of healthy control subjects. Most of the genes related to melanogenesis were down-regulated in patients (CREB1, MITF, LEF1, USF1, MAPK14, ICAM1, PIK3CB, RPS6KB1, KIT, and ATRN). Conversely, an up-regulation occurred in the case of opioids (PENK, PDYN, and PNOC). The suppression of genes related to melanogenesis is in agreement with the reported reduction in pigmentation signaling in psoriatic skin and potentially results from the pro-inflammatory environment. The increase in endogenous opioids can be associated with their involvement in inflammatory dysregulation in psoriasis.

P.0621 What renders people vulnerable to developing opioid addiction?

In non-human primates, opioid-receptor blockade increases social grooming, and the endogenous opioid system has therefore been hypothesized to support maintenance of long-term relationships in humans as well. Here we tested whether social touch modulates opioidergic activation in humans using in vivo positron emission tomography (PET). Eighteen male participants underwent two PET scans with [11C]carfentanil, a ligand specific to μ-opioid receptors (MOR). During the social touch scan, the participants lay in the scanner while their partners caressed their bodies in a non-sexual fashion. In the baseline scan, participants lay alone in the scanner. Social touch triggered pleasurable sensations and increased MOR availability in the thalamus, striatum, and frontal, cingulate, and insular cortices. Modulation of activity of the opioid system by social touching might provide a neurochemical mechanism reinforcing social bonds between humans.

MicroRNA-133b-3p Targets Purinergic P2X4 Receptor to Regulate Central Poststroke Pain in Rats

Central poststroke pain (CPSP) is a neuropathic pain syndrome that usually occurs after cerebrovascular accidents. Currently, the pathogenesis of CPSP is not fully understood. Purinergic P2X4 receptor (P2X4R) is implicated in neuropathic pain including CPSP. Herein, we demonstrated that the levels of microRNA-133b-3p (miR-133b-3p), which targets P2X4R transcripts, were significantly downregulated in the ventral posterolateral nucleus of the thalamus (VPL), cerebrospinal fluid (CSF), and plasma of CPSP rats. The expression levels of miR-133b-3p negatively correlated with the severity of allodynia. Genetic knockdown of P2X4R in the VPL protected CPSP rats against allodynia. Similarly, genetic overexpression of miR-133b-3p in the VPL reversed the allodynia established in CPSP rats via downregulation of P2X4R expression. Treatment using gabapentin in CPSP rats significantly restored the decreased miR-133b-3p expression in the VPL, CSF, and plasma and blocked allodynia in CPSP rats. The administration of an miR-133b-3p inhibitor into the VPL abolished the antiallodynic activity of gabapentin. This mechanism was associated with P2X4R expression and involved the endogenous opioid system. Human patients with CPSP showed decreased plasma levels of miR-133b-3p compared with those of control participants. Logistic regression analysis of our patient cohort showed that determining plasma levels of miR-133b-3p may be useful for CPSP diagnosis and treatment.

Depression, Anxiety, and Chronic Fatigue Symptoms in Acute Rheumatoid Arthritis Are Associated With Immune-Inflammatory, Autoimmune, Endogenous Opioid System and Lactosylceramide Signaling Pathways: A Nomothetic Network Approach

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms. To examine the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), and CFS-like (Fibro-fatigue Scale) symptoms and immune-inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylceramide in RA. Serum biomarkers were assayed in RA patients with (n=59) and without (n=59) increased psychopathology (PP) and 50 healthy controls. There were highly significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tenders and swollen joints, and patient and evaluator global assessment scores. A common latent vector (reflective model) could be extracted from the PP and RA-severity scales, which showed excellent psychometric properties. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning PP and RA symptoms could be explained by the regression on immune-inflammatory pathways, rheumatoid factor and anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels. Depression, anxiety, and CFS-like symptoms due to RA are reflective manifestations of the phenome of RA and are mediated via the effects of the same immune-inflammatory, autoimmune, and EOS pathways and lactosylceramide that underpin the pathophysiology of RA. These PP symptoms are clinical manifestations of the pathophysiology of RA. Funding Information: There was no specific funding for this specific study. Declaration of Interests: The authors declare no conflicts of interest which are relevant to the content of this article. Ethics Approval Statement: The ethics committee (IRB) of the University of Kufa, Iraq (243/2020), which complies with the International Guideline for Human Research Protection, approved the study as required by the Helsinki Declaration.

Broad opioid antagonism amplifies disruption of locomotor function following therapy-like hindlimb stretching in spinal cord injured rats

Preclinical pilot study. To test the hypothesis that spinal opioidergic circuitry contributes to muscle stretch-induced locomotor deficits. Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. A pilot study with eight female Sprague-Dawley rats that received 25 g-cm T10 contusion injuries and recovered for 5 weeks. Rats were divided into two groups with one group receiving subcutaneous injections of naltrexone dissolved in saline (15 mg/kg) or an equal volume of saline. Each group received a daily 24-minute stretching protocol during weeks 6, 8, and 11 post-injury. Locomotor function was assessed throughout using the BBB Open Field Locomotor Scale. Consistent with previous findings, stretching reduced locomotor function in both naltrexone and saline groups. However, the loss of locomotor function appeared earlier in the naltrexone group. Animals in both groups had a similar rate of recovery following the termination of stretching. Interestingly, the administration of naltrexone did not influence acute thermal cutaneous nociceptive responses as measured by a tail-flick assay but caused a significant increase in spasticity following stretch. The results of this study suggest that the endogenous opioid system plays a role in modulating the negative impact of muscle stretch on spinal cord motor circuitry that is vulnerable due to loss of descending input. The observed actions of the broad-spectrum opioid antagonist naltrexone imply that pharmaceuticals targeting the endogenous opioid system post-SCI may have unintended consequences.

The Role of Trauma in Early Onset Borderline Personality Disorder: A Biopsychosocial Perspective

The role of childhood trauma in the development of borderline personality disorder (BPD) in young age has long been studied. The most accurate theoretical models are multifactorial, taking into account a range of factors, including early trauma, to explain evolutionary pathways of BPD. We reviewed studies published on PubMed in the last 20 years to evaluate whether different types of childhood trauma, like sexual and physical abuse and neglect, increase the risk and shape the clinical picture of BPD. BPD as a sequela of childhood traumas often occurs with multiple comorbidities (e.g. mood, anxiety, obsessive-compulsive, eating, dissociative, addictive, psychotic, and somatoform disorders). In such cases it tends to have a prolonged course, to be severe, and treatment-refractory. In comparison with subjects who suffer from other personality disorders, patients with BPD experience childhood abuse more frequently. Adverse childhood experiences affect different biological systems (HPA axis, neurotransmission mechanisms, endogenous opioid systems, gray matter volume, white matter connectivity), with changes persisting into adulthood. A growing body of evidence is emerging about interaction between genes (e.g. FKBP5 polymorphisms and CRHR2 variants) and environment (physical and sexual abuse, emotional neglect).

Multiple Sclerosis and the Endogenous Opioid System.

Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation, neuronal degeneration and demyelinating lesions within the central nervous system. The mechanisms that underlie the pathogenesis and progression of MS are not fully known and current therapies have limited efficacy. Preclinical investigations using the murine experimental autoimmune encephalomyelitis (EAE) model of MS, as well as clinical observations in patients with MS, provide converging lines of evidence implicating the endogenous opioid system in the pathogenesis of this disease. In recent years, it has become increasingly clear that endogenous opioid peptides, binding μ- (MOR), κ- (KOR) and δ-opioid receptors (DOR), function as immunomodulatory molecules within both the immune and nervous systems. The endogenous opioid system is also well known to play a role in the development of chronic pain and negative affect, both of which are common comorbidities in MS. As such, dysregulation of the opioid system may be a mechanism that contributes to the pathogenesis of MS and associated symptoms. Here, we review the evidence for a connection between the endogenous opioid system and MS. We further explore the mechanisms by which opioidergic signaling might contribute to the pathophysiology and symptomatology of MS.

The expression of delta opioid receptor mRNA in adult male zebra finches (Taenopygia guttata).

The endogenous opioid system is evolutionarily conserved across reptiles, birds and mammals and is known to modulate varied brain functions such as learning, memory, cognition and reward. To date, most of the behavioral and anatomical studies in songbirds have mainly focused on μ-opioid receptors (ORs). Expression patterns of δ-ORs in zebra finches, a well-studied species of songbird have not yet been reported, possibly due to the high sequence similarity amongst different opioid receptors. In the present study, a specific riboprobe against the δ-OR mRNA was used to perform fluorescence in situ hybridization (FISH) on sections from the male zebra finch brain. We found that δ-OR mRNA was expressed in different parts of the pallium, basal ganglia, cerebellum and the hippocampus. Amongst the song control and auditory nuclei, HVC (abbreviation used as a formal name) and NIf (nucleus interfacialis nidopallii) strongly express δ-OR mRNA and stand out from the surrounding nidopallium. Whereas the expression of δ-OR mRNA is moderate in LMAN (lateral magnocellular nucleus of the anterior nidopallium), it is low in the MSt (medial striatum), Area X, DLM (dorsolateral nucleus of the medial thalamus), RA (robust nucleus of the arcopallium) of the song control circuit and Field L, Ov (nucleus ovoidalis) and MLd (nucleus mesencephalicus lateralis, pars dorsalis) of the auditory pathway. Our results suggest that δ-ORs may be involved in modulating singing, song learning as well as spatial learning in zebra finches.

Sex Differences in the Blood Oxygen Level-Dependent Signal to Placebo Analgesia and Nocebo Hyperalgesia in Experimental Pain: A Functional MRI Study.

ObjectivePlacebo as well as nocebo responses are widely found in scientific research and clinical practice. Growing evidence suggests sex differences in placebo as well as nocebo responses. However, data concerning this question are still insufficient. This study examined whether the BOLD signals of two responses, as measured with functional MRI (fMRI), differ by sex under conditions of equivalent experimental pain perception.MethodThirty-one healthy volunteers (14 female) underwent two fMRI scans, once during a placebo intervention and once during a nocebo intervention, pseudorandomly ordered, in an acute lower back pain (ALBP) model. We collected visual analog scale (VAS) data after each scanning. fMRI data from different sex groups were subjected to functional connectivity (FC) analysis and behavioral correlation analysis (BCA).ResultsThe results showed statistical differences in VAS scores between male and female participants, in both placebo and nocebo responses. Both groups also showed reduced FC in the pain-associated network of the placebo response and elevated FC in the pain-related network of the nocebo response. However, in the placebo condition, male participants displayed increased FC in the ventromedial prefrontal cortex, parahippocampal gyrus (PHP), and posterior cingulate cortex (PCC), while female participants showed increased FC in the dorsolateral prefrontal cortex, hippocampal gyrus (HP), and insular cortex (IC). In the nocebo condition, male participants showed decreased FC in the PCC and HP, while female participants displayed decreased FC in the mid-cingulate cortex, thalamus (THS), and HP. The BCA results of the two groups were also different.ConclusionWe found that the endogenous opioid system and reward circuit play a key role in sex differences of placebo response and that anxiety and its secondary reactions may cause the sex differences of nocebo response.

Stress and pain: modality-specific opioid mediation of stress-induced analgesia.

Preclinical research has demonstrated that exposure to acute stress is associated with attenuated pain perception, so called stress-induced analgesia (SIA). Mechanisms of SIA in humans have not been reliably demonstrated. This study examined the role of the endogenous opioid system in the impact of combined interpersonal and mental stressors on evoked pain responses in 84 participants (34 women). Using a within-subject, double-blinded, counterbalanced design, participants were administered either oral placebo or the opioid antagonist naltrexone (50mg) across two testing sessions. In each session, they experienced two evoked pain stimuli (cold pressor test [CPT], heat pain) after an extended rest period (rest condition) and after exposure to an acute stressor (a combination of public speaking and mental arithmetic challenge; stress condition). Results showed that both stress and opioid blockade produced significant changes in hormonal and cardiovascular measures, consistent with successful induction of acute stress. Stress was associated with attenuated pain perception (SIA) as indicated by significantly increased CPT tolerance. These effects were particularly pronounced in individuals experiencing the stress condition first. More importantly, SIA effects on CPT tolerance were abolished by opioid blockade. There were no significant SIA effects on heat pain responses. This study demonstrates that the endogenous opioid system may mediate effects of acute stress on pain perception, although this effect seems to be qualified by the type of evoked pain stimuli experienced.