Prostaglandin E receptor EP₃ subtype is involved in thermal hyperalgesia through its actions in the preoptic hypothalamus and the diagonal band of Broca in rats

The effects of microinjection of prostaglandin E₂ (PGE₂) (0.5 fg-500 pg/0.2 μl) into the medial part of the preoptic area (MPO) on nociception were studied using a hot-plate test in rats. The intraMPO microinjection of PGE₂ only at non-pyrogenic doses (5-50 fg) reduced the paw-withdrawal latency, suggesting hyperalgesia. Maximal reduction was obtained 15 min after the injection of PGE₂ at 50 fg. Subsequently, to determine which types of prostanoid receptors are involved in the hyperalgesic effect of PGE₂ in the MPO, we administered PGE₂ receptor agonists, i.e., 17-phenyl-ω-trinor PGE₂ (an EP₁ receptor agonist), butaprost (an EP₂ receptor agonist) and M and B28767 (an EP₃ receptor agonist) into the MPO and observed the nociceptive behavior. The intraMPO injection of M and B28767 (0.005 fg-50 pg), like that of PGE₂, exhibited a U-shaped dose response characteristic, i.e., a significant decrease of the paw-withdrawal latency only at 0.055 fg with the maximal response at 0.5 fg. However, neither the administration of EP₁ (0.5 fg-50 ng) nor EP₂ (0.5 fg-500 pg) agonists had any effect on nociception. The microinjection of M and B28767 at 0.5 fg into the other parts of preoptic hypothalamus (the lateral part of the preoptic area and the median preoptic nucleus) and the diagonal band of Broca (DBB) produced hyperalgesia similar to the intraMPO-induced hyperalgesia in terms of magnitude and time course. Microinjection of M and B28767 (0.5 fg) into either the paraventricular nucleus, the ventromedial hypothalamus, the lateral hypothalamic area or the septal nucleus had no effect on nociception. These findings suggest that PGE₂ at non-pyrogenic doses in the brain induces hyperalgesia, at least in part, through its actions on EP₃ receptors in the preoptic hypothalamus and the DBB in rats.