## 4 Discussion
Local hypoalgesic effects have been found near the exercised muscles [38, 39], and a systematic effect has been observed in remote areas from the exercised muscles, although the local hypoalgesic effects are stronger [40, 41]. Studies that examined the hypoalgesic effects accompanying lower extremities aerobic exercise have also shown inconsistent findings regarding pain thresholds in remote areas [34, 35, 42, 43, 44, 45, 46]. Decreased sensitivity to pain in distant regions may indicate systemic modulation mediated by endogenous inhibition mechanisms involving the descending inhibitory pathways [34]. In the present study, we chose to perform the pain measurements in a remote area (lower limb) to learn about the systemic effects of upper-limb exercise. The rationale was that we aimed to test whether the upper-limb exercise will reduce pain sensitivity in the lower limbs and thus may be suitable as a therapeutic tool for people suffering from leg pain of various types. The lack of hypoalgesic effects that we found in a healthy population may suggest that arm exercise is not applicable for clinical pain; however, further investigation of patient populations with lower-limb pain is needed. Various mechanisms have been suggested to explain EIH and the differences between lower and upper-limb exercise. However, the underlying mechanism is not yet fully understood [47]. The most widely discussed hypothesis for EIH is that of the endocrine system response to stress [47, 48]. There is growing evidence of an increase in stress hormones and hormones associated with the hypothalamic-pituitary-adrenal axis (HPA) following exercise, and their effect on pain sensitivity through a cascade of responses in the endocrine system [48, 49]. Considering this hypothesis, [PERSON] et al. compared pituitary-adrenal hormone levels (adrenoocortic hormone-ACTH, cortisol and beta-endorphin) in untrained young men after 30 min of upper-limb or lower-limb aerobic exercise. They found an increase in the hormonal concentrations after exertion of 80% of maximal oxygen consumption (rather than 60%) and no difference in hormonal concentrations between exercise in the upper limbs compared to the lower limbs [50]. This finding is consistent with a previous study by [PERSON] et al., who found an increase in beta endorphin only following aerobic exercise of at least 70% of maximal oxygen consumption [51]. We did not measure the concentration of such hormones directly in the current study; however, since the exercise carried out resulted in lactate accumulation above the OBLA point, it can be assumed that the exercise intensity was sufficient to activate the opioid mechanism. Nevertheless, this does not fully explain the EIH effects observed in studies at more moderate intensities. Another proposed mechanism for the EIH effect is related to increased blood pressure during exercise, which activates the endogenous-opioid system to reduce pain. The mechanism is not entirely clear, but one hypothesis is that the increase in blood pressure activates the barooreceptors in the carotid and the aortic arch that are innervated by vagal afferents, which transmit the neural response to structures responsible not only for cardiovascular activity but also for pain regulation [52, 53, 54]. Aerobic exercise of large muscle groups in the lower extremities elevate the cardiac output more than the upper extremities [55], which may explain the lack of hypoalgesic effects in our exercise protocol. PPT is the most common outcome measure in EIH studies [2, 56] demonstrating a very high test-retest reliability [44, 57] Conversely, HPT has moderate-good reliability [58, 59], and it is considered a less reliable outcome measure [59] with no consistent results following vigorous aerobic exercise [23, 35, 60, 61]. While THP has a good test-retest reproducibility, it has a high inter-subject variability [14]. Several studies have examined EIH using THP as an outcome measure [6, 23, 60, 62] and found a decrease in pain ratings after aerobic exercise, yet no change in PPT [6, 23].