Diurnal changes of tonic nociceptive responses in mice: evidence for a proalgesic role for melatonin

Diurnal variations in tonic pain reactions have been described in mice tested in Spring, but the underlying mechanisms are stillunknown. We tested the potential role of melatonin, a key hormone in the control of neuro-endocrine circadian rhythms. The experimentswere performed in male CBA/J mice housed under controlled temperature, humidity, and light (12/12 dark/light cycle) conditions, duringthe Light (7–10 a.m.) or Dark (7–10 p.m.) phases of the diurnal cycle. In a first group of experiments, animals were either pretreatedwith i.p. saline (controls) or with the melatonin receptor antagonist, luzindole (30 mg/kg), before the s.c. injection of a dilute formalinsolution into a hindpaw. In control animals, pain-related behavioral reactions (licking and flinching) were higher in the evening (Dark)than in the morning (Light), both during the first (0–10 min) and the second (11–55 min) phase of the response to s.c. formalin. Inanimals pre-treated with luzindole, no diurnal changes occurred, pain reactions in the Dark being similar to those of the Light Controlgroup. In a second group of experiments, artificial pinealectomy, obtained by exposing animals to continuous light for 48 h, also reducedpain reactions in the evening to levels comparable to those in the morning. Receptor autoradiography showed lower binding availabilityat spinal cord level in mice sacrificed during the Dark, as expected from the circadian pattern of melatonin secretion. A further significantdecrease of melatonin receptor binding was induced by noxious stimulation. These results suggest a proalgesic role of endogenousmelatonin in tonic pain.