Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3 kinases and Per1 expression in the rat suprachiasmatic nucleus
Abstract
Background and PurposeOpioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling.
Experimental ApproachA time-dependent effect of morphine (1mgkg(-1), i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [S-35]-GTPS binding assay.
Key ResultsMorphine stimulated a rise in pERK1/2 and pGSK3 levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN.
The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3 levels in the rat ventrolateral and dorsomedial SCN.
Conclusions and ImplicationsOur data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3.