Pharmacological blockade of PPAR isoforms increases conditioned fear responding in the presence of nociceptive tone

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPAR¿, PPARß/¿, PPAR¿) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPAR¿ (GW6471), PPARß/¿ (GSK0660) or PPAR¿ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPAR¿ and PPARß/¿ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPAR¿ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPAR¿ and PPARß/¿ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPAR¿ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.This research was funded by Conselho Nacional de Pesquisa (CNPq)—Brazil (#207530/2014-9) and Science Foundation Ireland (10/IN.1/B2976). JCG was funded by a PhD scholarship from Conselho Nacional de Pesquisa (CNPq)—Brazil, ALB was funded by Government of Ireland Postdoctoral Research Fellowship from the Irish Research Councilpeer-reviewe