Nociceptive responses in melatonin MT2 receptor knockout mice compared to MT1 and double MT1/MT2 receptor knockout mice

Melatonin, a neurohormone that binds to two G protein‐coupled receptors MT1 and MT2, 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.