Early Life Stress, Opioid, Sex Differences, Stress
Conditions
Keywords
mu opioid receptor, stress, early life stress, social behaviour, affiliative behaviour, sex differences, endocannabinoid system, morphine, opioid use disorder
Brief summary
The study aims to investigate sex differences in the effect of mu-opioid receptor (MOR) activation on stress response and social behaviour modulated by early life stress.
Detailed description
While opioid use disorder presents a rising public health concern, the underlying neurobiological mechanisms of substance use are not well understood. In animal studies, activation of the Mu Opioid Receptor (MOR) system has been shown to have stress-buffering effects and to decrease affiliative behaviour, which is in line with addiction models postulating impaired stress response and poor social interactions to be risk indicators for addiction pathogenesis. In humans however, this has not been consistently found. Importantly, behavioural pharmacology studies have often been restricted to male test subjects or have been underpowered. Therefore, a significant knowledge gap remains regarding sex-specific differences in MOR activation. The additional impact of chronic stress in the form of early life stress significantly affects brain development, in turn shaping stress reactivity and affiliative behaviour in later life. This forms the basis of the research question of the present study, whether sex and childhood unpredictability modulate the effects of MOR activation on stress response and social interaction behaviour. The prototypical opioid morphine will be used to activate the MOR. Participants will receive the study medication on two separate visits in a randomised, counterbalanced order. Afterwards, participants will conduct computer-based stress and social interaction tasks. Learning more about individual differences in MOR activation and its effects on stress and social behaviour can help to uncover vulnerability and risk factors for opioid use disorder and improve personalised treatment opportunities.
Interventions
DRUGMorphine
Sevredol 10mg, oral single-dose administration
DRUGPlacebo
identical in appearance to active drug, containing no active substance (mannitol), oral one-time administration
Sponsors
Sara L. Kroll
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Randomized, double-blind, placebo-controlled, crossover study
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-40 years * Ability to read, understand, and provide written informed consent in German * Proficiency in German * Able to give blood samples (no blood- or needle-related phobia) * Good health as determined by medical history, ECG, and clinical assessment of lab tests. Lab tests will include potassium, creatinine, hemoglobin, glucose, calcium, BUN, complete blood count, total bilirubin, AST, ALT, and GGT. The final decision will be according to the judgment of the study physician. * Females must have a negative urine pregnancy test (hCG) at inclusion and at the start of each study session. Females of childbearing potential who are sexually active and have not been surgically sterilized must agree to use an adequate method of birth control during the study. * Prior experience with medical opioids (at least one experience with prescription opioids such as oxycodone, morphine, hydromorphone, fentanyl, hydrocodone, codeine, or dihydrocodeine) and paracetamol. * Body mass index (BMI) between 19 and 30 kg/m2
Exclusion criteria
* Any current instable medical or neurological condition * Any clinically significant psychiatric disorder (i.e., psychotic and stress-related disorders) including a diagnosis of substance use disorder (defined in DSM-5 terms as Moderate or Severe). Participants will be screened using the Structured Clinical Interview - SCID for DSM-5). If indication is obtained that a clinically significant psychiatric disorder may be present, a full SCID will be carried out by appropriately trained staff. * Significant adverse reaction to prior opioid or paracetamol exposure * Reporting any illegal drug use \>15 life-time occasions and regular drug use during the last three months incl. the test period (except for nicotine and alcohol) * Any current use of CNS-active medications. * Current use of opioid analgesics, opioid use for \> 6 weeks (lifetime), or within the three months prior to study enrollment. * Fagerström Test of Nicotine Dependence (FTND) Score \> 5 (strong nicotine dependence) * Heavy alcohol use based on the Alcohol Use Disorder Identification Test (AUDIT) * Lifetime diagnosis of cardiac disease. * Clinically significant laboratory or ECG abnormality that could be a safety issue in the study * Acute or chronic respiratory issues (e.g., cold, flu, asthma, etc.) * Lifetime diagnosis of liver or kidney disease including moderate or severe renal impairment (creatinine clearance \< 50 ml/min) * Lifetime diagnosis of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or autism spectrum disorder according to DSM-5 * Diagnosis of a current episode of depression based on DSM-5 criteria * Current diagnosis of a moderate or severe substance use disorder according to DSM-5 * Daily cannabis consumption in the past three months * Use of psychotropic medication within the last 7 days * Participation in other pharmacological studies within the last 2 months * Alcohol use within the last 24 hours controlled by breathalyzer * Unable to provide a negative urine drug screen (cannabinoids, amphetamines, opiates and opioids, benzodiazepines, and cocaine). * Positive pregnancy test or nursing (self-report) * For women: irregular menstrual cycle or menopause
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in self-reported subjective stress over time | Throughout the experimental sessions (from before stress induction to 10, 20, 30, 60 and 105 minutes after stress onset, 7 times). | Sex-specific differences in morphine-mediated stress relief measured by changes in Visual Analogue Scales (VAS), ranging from 0-100 with the anchors " not at all " (0) and "extremely" (100) for the items: "I feel stressed", "I feel safe", "I feel relaxed", "I have a dry mouth", "I feel nauseous", "I feel confident", "I feel ashamed", "I feel vulnerable" |
| Self-reported feeling of shame post-stress | ~10 minutes after stress onset | Sex-differences in morphine effects on the Experiential Shame Scale (ESS) score, ranging from 25 -100, with higher values indicating stronger feelings of shame. |
| Changes in self-reported affect over time | Throughout the experimental sessions (from before stress induction to 10, 30, 60 and 105 minutes after stress onset, 6 times). | Sex-specific differences in morphine effects on changes of positive and negative affect measured using the Positive and Negative Affect Schedule (PANAS) scores. Scores for both subscales range from 10 to 50 with higher scores indicating stronger positive or negative affect, respectively. |
| Early life stress | Prior to enrollment | Modulation of the Questionnaire of Unpredictability in Childhood (QUIC) sum score on differences in primary outcomes. Scores range from 0-38 with higher scores indicating greater exposure to instability and unpredictability during childhood. |
| Self-report of subjective stress during stress exposure | During the experimental stress task | Sex-specific differences in the stress relieving effects of morphine compared to placebo. Subjective stress response will be measured by differences between self- and other condition in ratings using a 1-7 Visual Analogue Scale (VAS) with the anchors "not at all" (1) to "very much" (7) for the items "How secure do you feel?" and "How stressed do you feel?" throughout the stress task. |
| Endocrinological markers of stress response | Throughout the experiment sessions (baseline and approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples). | Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by changes in plasma concentrations of cortisol and endocannabinoids (2-AG, AEA, PEA, SEA, OEA). |
| Psychophysiological stress response of heart rate measured by electrocardiogram | During the experimental stress task | Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in heart rate (beats per minute). |
| Psychophysiological stress response of heart rate variability measured by electrocardiogram | During the experimental stress task | Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in heart rate variability. |
| Psychophysiological measure of sympathetic activity | During the experimental stress task | Sex-specific differences in the stress relieving effects of morphine compared to placebo measured by differences between self and other condition in skin conductance response (SCR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early life stress | Prior to enrollment | Modulation of the Questionnaire of Unpredictability in Childhood (QUIC) sum score on differences in secondary outcomes. Scores range from 0-38 with higher scores indicating greater exposure to instability and unpredictability during childhood. |
| Hair concentrations of chronic stress markers | At screening | Modulation of tonic endocannabinoid (2-AG, AEA, OEA, PEA, SEA) and glucocorticoid (cortisol, cortisone, ACTH) concentrations in hair on primary and secondary outcomes. |
| Personality traits | Single measure, during experimental session | Modulation of personality traits measured by the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI) on primary and secondary outcomes. Scores range from 0-48 per subscale. Higher scores indicate higher expression of the trait. |
| Trait assessment of loneliness | Single measure, during experimental session | Modulation of loneliness measured by the German version of the UCLA loneliness scale on primary and secondary outcomes. Scores can range from 20-80 with higher scores indicating greater feelings of loneliness. |
| Rosenberg Self Esteem Scale | Single measure, during experimental session. | Modulation of self-esteem measured by the Rosenberg Self Esteem Scale (RSES) on primary and secondary outcomes. Scores range from 0 -30 with scores below 15 suggesting low self-esteem, 15 to 25 reflecting a normal or average range, and 26 to 30 indicating high self-esteem. |
| Psychophysiological cardiac markers of social interaction measured by heart rate variability using electrocardiogram | During the experimental tasks | Sex-specific differences in morphine effects on heart rate variability during the social approach/avoidance task and the affective touch task. |
| Psychophysiological measure of sympathetic activity during social interaction | During the experimental tasks. | Sex-specific differences in morphine effects on skin conductance response (SCR) during the social approach/avoidance task and the affective touch task. |
| Subjective differences in experiencing social interaction | During the experimental tasks | Sex-specific differences in morphine effects on subjective pleasantness ratings measured by VAS scales (1-100) during the social approach/avoidance task and affective touch task with higher ratings indicating more pleasantness. |
| Behavioural differences of social approach and avoidance | During the experimental task | Sex-specific differences in morphine effects on behavioural measures (measured by number of button presses) during the social approach/avoidance task. |
| Psychophysiological cardiac markers of social interaction measured by heart rate using electrocardiogram | During the experimental tasks | Sex-specific differences in morphine effects on heart rate (beats per minute) during the social approach/avoidance task and the affective touch task. |
| Socioeconomic status ladder | Single measure, during experimental session. | Modulation of socioeconomic status (SES) measured by the MacArthur SES ladder on primary and secondary outcomes. Participants rate their perceived socioeconomic status and social standing using two ladder scales ranging from 1-10: one relative to people in Switzerland and one relative to people in their community. Higher scores indicate higher perceived socioeconomic status or social standing. |
| Brief Resilience Scale | Single measure, during experimental session. | Modulation of resilience measured by the Brief Resilience Scale (BRS) on primary and secondary outcomes. Scores range from 1-5 with a higher score indicating a better ability to bounce back after stress. |
| Sex hormone concentration | Single measure at both experimental sessions. | Modulation of baseline concentrations of steroid sex hormones (testosterone, progesterone, estradiol) in plasma on primary and secondary outcomes. |
| Becker Depression Inventory | Single measure, during experimental session. | Modulation of depression measured by the Becker Depression Inventory (BDI-II) on primary and secondary outcomes. Scores range from 0-63 with higher scores indicating more severe depressive symptoms. |
| Trait anxiety level | Single measure, during experimental session. | Modulation of anxiety measured by the State Trait Anxiety Inventory (STAI) on primary and secondary outcomes. Scores range from 20-80 per subscale, with higher scores indicating higher levels of trait anxiety. |
| Snaith Hamilton Anhedonia Pleasure Scale | Single measure, during experimental session. | Modulation of anhedonia measured by the Snaith Hamilton Anhedonia Pleasure Scale (SHAPS) on primary and secondary outcomes. Scores range from 0-14 with higher scores indicating less ability to feel pleasure. |
| Relationship Structures Questionnaire | Single measure, during experimental session. | Modulation of attachment style measured by the Experiences in Close Relationship Structures Questionnaire (ECR-RS) on primary and secondary outcomes. Two scores, one for attachment-related avoidance and the other for attachment-related anxiety, are computed for different interpersonal targets. The avoidance score can be computed by averaging items 1 - 6 and the anxiety score by averaging items 7 - 9, respectively. |
| State anxiety over time | Throughout the experimental sessions (from before stress induction to approx. 10, 30, 60, and 105 minutes after stress onset, 6 times). | Sex-specific differences in morphine effects on changes in state anxiety measured by the State-Trait Anxiety Inventory (STAI) score. Scores can range from 20 -80 with higher scores indicating greater anxiety |
| Drug Effects Questionnaire (DEQ) | Throughout the experimental sessions (immediately after drug administration until approx. 3 hours after study medication administration, 7 times). | Sex-specific differences in drug effects will be measured using the Drug Effects Questionnaire (DEQ; subjective experiences are reported of "feeling the drug", "feeling high", "drug liking" and "disliking", and "desire to take the drug again") measured on an electronic 0-100 VAS, anchors "not at all" and "extremely". |
| Drug concentration | Throughout the experimental sessions (from 1 hour after drug administration until approx. 3 hours after study medication administration, 4 samples). | Differences in concentration of the study drug in blood between the two test sessions. |
| Changes in oxytocin over time | Throughout the experimental sessions (from before stress induction to approx. 10, 20, 30, 60 and 105 minutes after stress onset, 6 samples). | Sex-specific differences in morphine effects on oxytocin levels measured in saliva. |
Countries
Switzerland
Contacts
CONTACTSara L Kroll, Dr. phil.
CONTACTElla L Sommer
PRINCIPAL_INVESTIGATORSara L Kroll, Dr.
Psychiatric University Hospital, Zurich
Outcome results
None listed