Endogenous opioid signaling in the retina modulates sleep/wake activity in mice

Abstract

Circadian sleep/wake rhythms are synchronized to environmental light/dark cycles in a process known as photoentrainment. We have previously shown that activation of β-endorphin-preferring μ-opioid receptors (MORs) inhibits the light-evoked firing of intrinsically photosensitive retinal ganglion cells (ipRGCs), the sole conduits of photoentrainment. Although we have shown that β-endorphin is expressed in the adult mouse retina, the conditions under which β-endorphin is expressed are unknown. Moreover, it is unclear whether endogenous activation of the MORs expressed by ipRGCs modulates the photoentrainment of sleep/wake cycles. To elucidate this, we first measured the mRNA expression of β-endorphin's precursor, proopiomelanocortin (POMC), at various times of day by quantitative reverse-transcription PCR. POMC mRNA appears to have cyclic expression in the mouse retina. We then studied β-endorphin expression with immunohistochemistry and found that retinal β-endorphin is more highly expressed in the dark/at night. Finally, we used telemetry to measure activity, EEG and EMG in freely moving animals to compare sleep/wake cycles in wild-type and transgenic mice in which only ipRGCs lack functional MORs. Results from these experiments suggest that the MORs expressed by ipRGCs contribute to the induction and maintenance of activity in the dark phase in nocturnal mice, via the promotion of wakefulness and inhibition of slow-wave sleep. Together, these data suggest that endogenous β-endorphin activates MORs expressed by ipRGCs to modulate sleep/wake activity via the photoentrainment pathway.