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

Abstract

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.

Keywords: Gastrointestinal tract; Melatonin; Neu-P11; Neu-P12; Opioid; Visceral pain.

Figure 1

Effects of melatonin and melatonergic agonists on mustard oil-induced pain. A: Ip melatonin, Neu-P11, and Neu-P12 (all 25 and 50 mg/kg) reduced the number of pain-related behaviors in the mustard oil (MO) sensitivity test 15 min after drug administration; B: Oral melatonin, Neu-P11 and Neu-P12 (all 25 mg/kg, 50 mg/kg and 100 mg/kg) decreased the number of pain-related behaviors in the MO sensitivity test 20 min after drug administration; C: Effect of ip injected melatonin, Neu-P11 and Neu-P12 (all at 50 mg/kg) on the number of pain-related behaviors in the MO sensitivity test at 15 min, 2 and 4 h after drug administration. Data are mean ± SE (n = 6-10). ^bP < 0.01 vs MO; ^cP < 0.05, ^dP < 0.01 vs vehicle + MO; ^eP < 0.05, ^fP < 0.01 vs drug; ^gP < 0.05, ^hP < 0.01 vs control.

Figure 2

Effect of naloxone and melatonergic antagonists on melatonin, Neu-P11 and Neu-P12-induced effects on mustard oil-induced pain. A: Effects of antagonists: ip naloxone (1 mg/kg), but not luzindole (5 mg/kg) or 4-P-PDOT (4 mg/kg) blocked the effects of melatonin, Neu-P11, and Neu-P12 (all at 25 mg/kg, ip) on the number of pain-related behaviors in the mustard oil sensitivity test 15 min after drug administration; B: Icv naloxone (5 μg/animal), luzindole (5 μg/animal) and 4-P-PDOT (10 μg/animal) blocked the effects of melatonin, Neu-P11 and Neu-P12 (all at 25 mg/kg, ip) in the mustard oil sensitivity test 15 min after drug administration. Data are mean ± SE (n = 6-10). ^aP < 0.05, ^bP < 0.01 vs control; ^cP < 0.05 vs drugs + vehicle; ^eP < 0.05, ^fP < 0.01 vs vehicle icv + drugs ip.

Figure 3

Melatonin, Neu-P11 and Neu-P12 decreased the number of pain-related behaviors. A: Melatonin, Neu-P11 and Neu-P12 (all at 25 mg/kg, ip) decreased the number of pain-related behaviors in the capsaicin-induced visceral pain test 15 min after drug administration; B: Melatonin, Neu-P11 and Neu-P12 (all 5 at mg/kg, ip) decreased the number of pain-related behaviors in the writhing test 15 min after drug administration. Data are mean ± SE (n = 6-10). ^aP < 0.05, ^bP < 0.01 vs control.