How Does the Opioid System Shape Stress and Social Behaviour in Men and Women and What Role Does Childhood Unpredictability Play?

Randomized, Double-blind, Placebo-controlled, Crossover Study Investigating Sex-specific Effects of Mu-opioid Receptor Activation on Stress and Social Interaction and Its Modulation by Early Life Stress

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.

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.

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