Dopamine D₁ and D₂ receptors mediate neuropeptide S-induced antinociception in the mouse formalin test

Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor named NPS receptor. The NPS system controls several biological functions, including anxiety, wakefulness, locomotor activity, food intake, and pain transmission. A growing body of evidence supports facilitatory effects for NPS over dopaminergic neurotransmission. The present study was aimed to investigate the role of dopamine receptors signaling in the antinociceptive effects of NPS in the mouse formalin test. The following dopamine receptor antagonists were employed: SCH 23390 (selective dopamine D₁ antagonist, 0.05 mg/kg, ip), haloperidol (non-selective dopamine D₂-like receptor antagonist; 0.03 mg/kg, ip), and sulpiride (selective dopamine D₂-like receptor antagonist; 25 mg/kg, ip). Mice were pretreated with dopamine antagonists before the supraspinal administration of NPS (0.1 nmol, icv). Morphine (5 mg/kg, sc) and indomethacin (10 mg/kg, ip) were used as positive controls to set up the experimental conditions. Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was only active at phase 2. Central NPS significantly reduced formalin-induced nociception during both phases. The systemic administration of SCH 23390 slightly blocked the effects of NPS only during phase 2. Haloperidol prevented NPS-induced antinociceptive effects. Similar to haloperidol, sulpiride also counteracted the antinociceptive effects of NPS in both phases of the formalin test. In conclusion, the present findings suggest that the analgesic effects of NPS are linked with dopaminergic neurotransmission mainly through dopamine D₂-like receptor signaling.