Physical exercise is increasingly recognized as an effective treatment for chronic pain. Studies in humans and animals have shown that a single session of exercise induces a reduction of sensitivity to experimental painful stimuli lasting up to 45 minutes. In a recent study conducted in our laboratory, we found (1) that this exercise- induced hypoalgesia (EIH) is mainly driven by local changes in muscle nociceptor sensitivity within exercising muscles and (2) that EIH is consistent at a group level but fluctuates across sessions within participants. The first aim of this project is to uncover the mechanism(s) that drive EIH by investigating whether processes that could contribute to an exercise-induced change in muscle nociceptor sensitivity match the fluctuating pattern of EIH. Specifically, we will assess the possible involvement in EIH of the endocannabinoid system (eCB), Kynurenic acid (KynA, a circulating myokine that transiently increases after exercise), and β -endorphins (βE). Using a sample of 90 healthy males and females aged 18 to 30 years, we will measure sensitivity to blunt pressure stimuli before, immediately after, and 45 min after a 25-min cycling exercise to assess muscle nociceptor sensitivity at exercising (rectus femoris muscle) and non-exercising (ventral forearm) muscles. Blood samples will be collected at these time-points to measure plasma levels of eCBs, βE, and KynA. In addition, the effect of sex on EIH is controversial: some studies report no differences between males and females, while others report a greater effect in males or in females. Therefore, a secondary aim of this study is to explore potential sex differences in the manifestation and underlying mechanism(s) of EIH.

Inclusion Criteria:

• Males, or females using hormonal contraception since ≥ 3 months.
• Aged between 18 and 30 years.
• Ability to provide written informed consent.
• Fluency in French or English.
• BMI between 17 and 30 kg/cm2.

Exclusion Criteria:

• Regular tobacco use (> 1/month)
• Not willing or able to abstain from alcohol, recreational drugs, coffee, or tea from 24 hours prior to each experimental session.
• Not willing or able to restrain from physical activity > 24h prior to each experimental session, and to be in a fasted state on the day of each experimental session.
• Any evidence for neurological, cardiovascular, respiratory, inflammatory, endocrine, psychiatric, oncological, rheumatological conditions on direct questioning.
• Presence of any medical devices (e.g., cardiac pacemaker) implants or prothesis unless it is beyond discussion that these will not put the subject's safety during the study at risk and will not interfere with the results of the study.
• Any chronic pain condition or recent history thereof (i.e., within the preceding 2 years).
• Wounds or skin alteration on testing sites.
• Surgery < 12 months.
• Any drug intake in the past 2 weeks including antibiotics, herbal medicines and other remedies except the following drugs that will be allowed up to 48 hours prior to the experiments: oral paracetamol or ibuprofen for a self-limiting condition (e.g. toothache, bruise). Oral antihistaminics and nasal aerosol and topical treatments for seasonal allergy up to 1 week before the experimental session.
• Any physical activity contraindication.
• Pregnancy.

• Participant will be masked to study hypotheses
• Outcome assessor/Investigator will be masked to sensory tests results