Abstract
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.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and part of the nuclear hormone superfamily of receptors
Systemic Administration of PPARα and PPARβ/δ Antagonists Had no Effect on Formalin-Evoked
Our results suggest that endogenous signalling at PPARα, PPARβ/δ and PPARγ does not mediate or modulate formalin-evoked nociceptive behaviour
Summary
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and part of the nuclear hormone superfamily of receptors. There are three described isoforms: PPARα, PPARβ/δ and PPARγ [1]. All three isoforms are expressed in the brain and spinal cord [2]. Endogenous ligands at PPARs, include fatty acids [3], serotonin derivates [4], and N-acylethanolamines (NAEs) including anandamide (AEA) [5,6], N-palmitoylethanolamide (PEA) [7] and N-oleoylethanolamide (OEA) [8]. PPARs are involved in many physiological processes and are targets for currently in-use medicines for diabetes [9]. Molecules 2020, 25, 1007 and lowering cholesterol therapies [10]. Studies suggest that the PPAR signalling system may act as a modulator of pain [11], anxiety [12] and cognition [13,14,15]
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