Antinociceptive effects of novel melatonin receptor agonists in mouse models of abdominal pain.

Aim: To characterize the antinociceptive action of the novel melatonin receptor (MT) agonists, Neu-P11 and Neu-P12 in animal models of visceral pain.
Methods: Visceral pain was induced by intracolonic (ic) application of mustard oil or capsaicin solution or by intraperitoneal (ip) administration of acetic acid. Neu-P11, Neu-P12, or melatonin were given ip or orally and their effects on pain-induced behavioral responses were evaluated. To identify the receptors involved, the non-selective MT1/MT2 receptor antagonist luzindole, the MT2 receptor antagonist 4-P-PDOT, or the μ-opioid receptor antagonist naloxone were injected ip or intracerebroventricularly (icv) prior to the induction of pain.
Results: Orally and ip administered melatonin, Neu-P11, and Neu-P12 reduced pain responses in a dose-dependent manner. Neu-P12 was more effective and displayed longer duration of action compared to melatonin. The antinociceptive effects of Neu-P11 or Neu-P12 were antagonized by ip or icv. administered naloxone. Intracerebroventricularly, but not ip administration of luzindole or 4-P-PDOT blocked the antinociceptive actions of Neu-P11 or Neu-P12.
Conclusion: Neu-P12 produced the most potent and long-lasting antinociceptive effect. Further development of Neu-P12 for future treatment of abdominal pain seems promising.