The effects of peripheral administration of a novel selective antagonist for prostaglandin E receptor subtype EP1, ONO-8711, in a rat model of postoperative pain

Mechanically evoked pain, also known as incident pain, induced by coughing or deep breathing after surgery leads to potentially devastating consequenc es. It is generally thought that the prostaglandin receptor- (especially, t he receptor for prostaglandin E-2, EP receptor) mediated sensitization of s ensory nerve fibers is a key contributor to the generation of hyperalgesia. We examined whether a peripherally administered novel selective EP1 antago nist, ONO-8711, would be a potential analgesic for incision-induced mechani cal hyperalgesia. We used a rat model of postoperative pain introduced by B rennan et al. (1). Withdrawal thresholds to punctate stimulation and respon se frequencies to nonpunctate mechanical stimulation were determined by usi ng von Frey filaments applied adjacent to the wound and directly to the inc ision site of the hind paw, respectively. Mechanical hyperalgesia to puncta te and nonpunctate stimuli was observed 2 and 24 h after the incision. ONO- 8711 (2, 10, or 50 mug) or saline was administered subcutaneously into the hind paw on the ipsilateral side to the incision. ONO-8711 significantly (P < 0.01) increased the withdrawal thresholds to punctate mechanical stimula tion and significantly (P < 0.01) decreased the response frequencies to non punctate mechanical stimulation in a dose and time-dependent manner 2 and 2 4 h after the incision. We conclude that EP1 receptor-mediated sensitizatio n of sensory nerve fibers may contribute to the generation of mechanical hy peralgesia produced by incisional surgery, and that the EP1 receptor antago nist ONO-8711 may be an option for treatment of postoperative pain, especia lly incident pain.