Enadoline, a selective kappa-opioid receptor agonist shows potent antihyperalgesic and antiallodynic actions in a rat model of surgical pain

Pain. 1999 Mar;80(1-2):383-9. doi: 10.1016/s0304-3959(98)00237-1.


Enadoline is a highly selective and potent kappa-opioid receptor agonist. This report describes and compares the activities of enadoline and morphine in a rat model of postoperative pain. A 1 cm incision through the muscle and skin of the plantar surface of the right hind paw induced thermal hyperalgesia as well as static and dynamic allodynia lasting at least 2 days. Postoperative testing was carried out using the plantar test for thermal hyperalgesia, von Frey hairs for static allodynia and light stroking with a cotton bud for dynamic allodynia. A single i.v. dose of enadoline 15 min before surgery dose-dependently (1-100 microg/kg) blocked the development of thermal hyperalgesia as well as static and dynamic allodynia for over 24 h with respective MEDs of < or = 1, 10 and 10 microg/kg. The administration of enadoline (100 microg/kg, i.v.), 1 h after surgery, completely blocked the maintenance of the hyperalgesic and allodynic responses, but its duration of action was much shorter (2 h) than when administered before surgery. Previous studies have shown that administration of morphine (1-6 mg/kg, s.c.) 0.5 h before surgery can prevent the development of thermal hyperalgesia with a MED of < or =1 mg/kg, but it has little effect on static allodynia. In the present study similar administration of morphine (1-3 mg/kg), unlike enadoline, had no effect on the development of dynamic allodynia. Morphine dose-dependently (1-6 mg/kg, s.c.) potentiated isoflurane-induced sleeping time and respiratory depression in the rat. However, whilst enadoline also (1-1000 microg/kg, i.v.) potentiated isoflurane-induced sleeping time, it did not cause respiratory depression. It is suggested that enadoline may possess therapeutic potential as a pre-emptive antihyperalgesic and antiallodynic agent.

MeSH terms

  • Anesthesia Recovery Period
  • Animals
  • Benzofurans / therapeutic use*
  • Blood Gas Analysis
  • Disease Models, Animal
  • Hot Temperature
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / physiopathology
  • Male
  • Morphine / pharmacology
  • Pain, Postoperative / drug therapy*
  • Pain, Postoperative / physiopathology
  • Pyrrolidines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / agonists*
  • Respiratory Mechanics / drug effects
  • Skin / physiopathology
  • Touch


  • Benzofurans
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Morphine
  • enadoline