Regulation of fear, anxiety and cognition in the presence or absence of pain by peroxisome proliferator-activated receptors

Fear/anxiety and pain modulate one another reciprocally, but the neurobiological mechanisms that underlie this interaction are not completely understood. Fear-conditioned analgesia (FCA) is pain suppression upon exposure to a fearful stimulus. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that modulate in pain, anxiety, and cognition. However, their role in pain-fear/anxiety interactions is unknown. The basolateral amygdala (BLA) and the central nucleus of the amygdala (CeA) play a key role in pain, conditioned fear and FCA. The overall aim of this thesis was to investigate the role of PPARa, PPARb/d and PPARg in acute and chronic inflammatory pain, conditioned fear, FCA, anxiety and cognition. In addition, the influence of pain on PPAR-mediated modulation of conditioned fear, innate anxiety and cognition was investigated. The FCA protocol combined footshocks with context and formalin-injection into the hind paw. On conditioning days, Male Sprague-Dawley rats received footshocks in a conditioning arena, while control rats were placed in the arena for an equivalent amount of time (9min 30secs; no footshocks). 23.5 hours later, rats received an intraplantar injection of formalin into the right hind paw. Rats received either intraperitoneal or intra-amygdalar injection of vehicle or PPARa, PPARb/d or PPARg antagonists prior to re-exposure to the arena and pain and fear-related behaviours were recorded for 15 or 30 minutes. In the final study, rats received intraplantar injections of complete Freund’s adjuvant (CFA), or only needle insertion, into the right hind paw; they received an intraperitoneal injection of vehicle, PEA, or PPARa, PPARb/d or PPARg antagonists and underwent pain (von Frey) and anxiety (elevated plus maze, open field, and light-dark box) tests on days 1, 7, 21 and 28 (pain) and 21 (anxiety), and a novel object recognition protocol on days 26-28. The key results indicated that the blockade of PPAR signalling, particularly PPARa and PPARg in the BLA, but not CeA, prolonged or enhanced contextually induced freezing behaviour in the presence of formalin-evoked nociceptive tone. In the absence of nociceptive tone, the blockade of PPARs in the BLA increased freezing expression in non-fear-conditioned rats, indicating a possible modulatory role of PPARs in innate anxiety. These results were associated with increased tissue levels of dopamine in the right BLA. The systemic administration of a PPARa antagonist impaired spatial memory of rats in the presence, but not in the absence, of chronic inflammatory pain induced by CFA. Systemic, intra-BLA or intra-CeA administration of PPAR antagonists did not alter formalin-evoked nociceptive behaviour, FCA or mechanical allodynia in the CFA model. In conclusion, these findings indicate a key role for PPARs in the BLA in mediating and modulating innate and conditioned fear behaviour, effects dependant on the presence or absence of nociceptive stimuli. Furthermore, PPARa signalling appears to enhance deficits in cognitive responses in the presence of chronic inflammatory pain. Taken together these data add to the body of knowledge on the role of PPARs in pain, fear and cognition and their interactions.2023-06-0