Cyclooxygenase and prostaglandin E2 at rest, during exercise and across extremes of temperature within healthy humans: The influence of acetaminophen

Global temperatures are continuing to rise whilst there are still extremes of cold to be endured. In these extremes of temperature, occupational pursuits and (ultra)endurance events are becoming more arduous and popular respectively. Indeed, within both occupational and exercise settings, exposure to extreme heat (e.g. exercise heat stress) is often preceded and/or followed by extreme cold [e.g., cold-water immersion (CWI)]. During such extremes, various integrated thermoregulatory mechanisms are employed to maintain homeostatic human core temperature (Tc) at ~37 °C. One mechanism that is currently poorly characterised and understood, is the cyclooxygenase (COX) prostaglandin E2 (PGE2) pathway. PGE2 is synthesised from one of the two COX isoforms (COX1, COX2) and is the mediator of fever.

Below the thermoneutral zone (TNZ), COX/PGE2 are implicated in afebrile thermoregulation in mice and humans. In mice, acetaminophen (ACT) decreased Tc by ~3 °C alongside ~96% reductions in PGE2. Following ACT ingestion in humans: (i) at an ambient temperature of 20°C Tc decreased by ~0.19 °C; and (ii) at an ambient temperature of 10 °C Tc decreased by ~0.42 °C; Tc remained stable in placebo conditions. The data from humans lacks analysis of COX/PGE2 concentrations, hence the poor understanding of whether the COX/PGE2 pathway is implicated within humans during in the defence of Tc in light of temperature challenge.

Therefore, this thesis aims to determine whether the COX/PGE2 pathway is implicated in human Tc defence/regulation during exposure to temperature extremes (cold and hot) and during exercise-heat stress. Additionally, whether ACT alters COX/PGE2 behaviour and thus thermoregulation (e.g. Tc) during these exposures will also be explored. To do this, thesis themes are broadly introduced in Chapter 1 and critically reviewed in Chapter 2. In Chapter 3 the common methods used throughout the thesis are described in full. Nuanced experimental chapter specific methods are included within the respective chapters. Five individual research studies are presented in chapters 4.0 to 8.0 (experimental chapters). The thesis is concluded with general discussion and future research directions sections in Chapter 9. [...]