Leknes, S. | Search bioRxiv

bioRxiv2024

Simulating a medical expertise: a robust novel stress induction paradigm in chronic pain patients

Maladaptive stress responses may exacerbate chronic widespread pain (CWP) and deserve further investigations. Yet, existing stress induction paradigms lack relevance for individuals with this condition. Hence, we developed the Social Benefits Stress Test (SBST), adapted from the Trier Social Stress Test. Instead of a job interview, the main task consists in justifying the inability to work. Forty women with CWP in the context of hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorders were included. They underwent a 30-min baseline, the new stress task and a recovery period. The psychophysiological stress response was captured using self-reported stress ratings, salivary cortisol and - amylase levels, as well as continuous physiological monitoring of heart rate variability (HRV) and electrodermal activity (EDA). Compared to baseline, the analysis revealed a significant and transient increase in stress ratings during the stress task, associated with a peak in salivary biomarkers concentrations. The HRV signal analysis showed a significant decrease in high frequency power (HF), and increases in heart rate, low frequency power (LF) and in LF/HF ratio. The EDA analysis revealed a significant increase in skin conductance level (SCL) tonic component and skin conductance response (SCR). Subjective stress ratings positively correlated with changes in salivary biomarkers, LF/HF ratio and EDA outcomes. The SBST induced a reproducible moderate stress response across subjective and physiological measures in a population of CWP patients, validating this task as a relevant experimental model of social stress in chronic pain. The SBST is a useful tool to study the relationship between stress and chronic pain. PerspectiveThis manuscript presents the Social Benefits Stress Test (SBST) as a novel paradigm to assess stress reactivity in chronic widespread pain patients. By simulating the challenge of justifying work incapacity, it elicits a reproducible stress response, supporting its use as a model to study stress-pain interactions and evaluate therapeutic interventions.

neuroscience↗

bioRxiv2022

Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade

Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session ([~]60 minutes), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for [~]30 minutes. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.

neuroscience↗