Melatonin, a neurohormone that binds to two G protein-coupled receptors MT₁ and MT_2, is involved in pain regulation, but the distinct role of each receptor has yet to be defined. We characterized the nociceptive responses of mice with genetic inactivation of melatonin MT₁ (MT₁ ^-/- ), or MT₂ (MT₂ ^-/- ), or both MT₁ /MT₂ (MT₁ ^-/- /MT₂ ^-/- ) receptors in the hot plate test (HPT), and the formalin test (FT). In HPT and FT, MT₁ ^-/- display no differences compared to their wild-type littermates (CTL), whereas both MT₂ ^-/- and MT₁ ^-/- /MT₂ ^-/- mice showed a reduced thermal sensitivity and a decreased tonic nocifensive behavior during phase 2 of the FT in the light phase. The MT₂ partial agonist UCM924 induced an antinociceptive effect in MT₁ ^-/- but not in MT₂ ^-/- and MT₁ ^-/- /MT₂ ^-/- mice. Also, the competitive opioid antagonist naloxone had no effects in CTL, whereas it induced a decrease of nociceptive thresholds in MT₂ ^-/- mice. Our results show that the genetic inactivation of melatonin MT₂ , but not MT₁ receptors, produces a distinct effect on nociceptive threshold, suggesting that the melatonin MT₂ receptor subtype is selectively involved in the regulation of pain responses.

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