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 (PPARα, PPARβ/δ, PPARγ) 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, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (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 PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ 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.

Classical conditioning of analgesic and hyperalgesic pain responses without conscious awareness

Pain reduction and enhancement can be produced by means of conditioning procedures, yet the role of awareness during the acquisition stage of classical conditioning is unknown. We used psychophysical measures to establish whether conditioned analgesic and hyperalgesic responses could be acquired by unseen (subliminally presented) stimuli. A 2 × 2 factorial design, including subliminal/supraliminal exposures of conditioning stimuli (CS) during acquisition/extinction, was used. Results showed significant analgesic and hyperalgesic responses (P < 0.001), and responses were independent of CS awareness, as subliminal/supraliminal cues during acquisition/extinction led to comparable outcomes. The effect was significantly larger for hyperalgesic than analgesic responses (P < 0.001). Results demonstrate that conscious awareness of the CS is not required during either acquisition or extinction of conditioned analgesia or hyperalgesia. Our results support the notion that nonconscious stimuli have a pervasive effect on human brain function and behavior and may affect learning of complex cognitive processes such as psychologically mediated analgesic and hyperalgesic responses.