Opioid induced non-photic phase shifts of hamster circadian activity rhythms.

The phase of the circadian pacemaker in hamsters can be shifted by the application of certain non-photic stimuli late in the subjective day. A projection from the intergeniculate leaflet of the thalamus to the circadian pacemaker in the suprachiasmatic nucleus is believed to mediate some types of non-photic phase-shifting stimuli. In hamsters, this projection is immunoreactive to both Neuropeptide Y and enkephalin. Previous work in other laboratories has shown that Neuropeptide Y administration is capable of phase shifting circadian rhythms without the application of light. The present study was undertaken to determine if enkephalinergic compounds likewise have the ability to non-photically phase shift hamster activity rhythms. Hamsters were maintained under conditions of constant darkness and circadian wheel running activity was recorded. Agonists and antagonists selective for kappa, mu, and delta opioid receptors were systemically applied without light to hamsters at circadian times 8 and 10 to determine if they were able to elicit phase shifts in wheel running activity rhythms. Of the compounds tested, only the delta opioid agonist BW373U86 significantly affected circadian phase. BW373U86 phase advanced hamster wheel running activity rhythms by approximately 45 min, although total activity levels following drug application were not significantly affected. Changes in the amount of wheel running activity were detected after administration of some mu and kappa opioids, although the circadian phase was not altered. These results indicate that enkephalin-mimetic delta opioid agonists are capable of producing non-photic phase shifts in hamster activity rhythms, and that opioids can independently affect circadian phase and activity levels in hamsters.

Effects of the 5HT1A agonist/antagonist BMY 7378 on light-induced phase advances in hamster circadian activity rhythms during aging.

The entrainment of some circadian rhythms in rodents and humans to the environmental light-dark cycle deteriorates during aging. Recent evidence suggests that the time-keeping ability of the circadian pacemaker maintains its endogenous period in both hamsters and humans. This suggests that any changes in the coupling between environmental cues and the circadian pacemaker are not due to changes in "clock speed," but rather due to a weakened coupling between the afferent systems relaying environmental information and the circadian pacemaker located in the suprachiasmatic nucleus. The suprachiasmatic nucleus receives serotonergic input from the raphe nuclei, and serotonergic 5HT1A,7 agonists have been reported to lose their circadian phase-adjusting efficacy during aging in hamsters. In the present study, the authors report the effects of a novel serotonergic agonist BMY 7378 on light-induced phase advances during aging in the hamster. The present report demonstrates that BMY 7378 is a highly efficacious chronobiotic that more than doubles the magnitude of light-induced phase shifts in hamster wheel-running activity rhythms. Light-induced phase advances in hamster wheel-running activity of at least 6 h following a single systemic dose of BMY 7378 are routinely observed. Furthermore, BMY 7378 potentiation of phase shifts is maintained in old hamsters, suggesting that BMY 7378 has a different site of activity than previously reported 5HT1A,7 agonists that have a diminished effect on circadian phase during aging.

SNC 80, a delta-opioid agonist, elicits phase advances in hamster circadian activity rhythms.

Non-photic stimuli administered to hamsters during the subjective day can cause phase advances in circadian wheel running activity. It is believed that afferent projections from the intergeniculate leaflet of the thalamus to circadian pacemaker cells within the suprachiasmatic nucleus mediate the phase shifting effects of some non-photic stimuli. In hamsters, many of the intergeniculate leaflet afferents contain enkephalin, yet the role of opioids in producing non-photic phase shifts in hamsters has not been reported. In the present study, we show that SNC 80, an agonist for the delta opioid receptor subtype, will phase advance hamster wheel running activity rhythms when administered late in the subjective day. These results indicate that opioids may be involved in modulating the circadian pacemaker in hamsters.

Distribution of delta opioid receptor immunoreactivity in the hamster suprachiasmatic nucleus and intergeniculate leaflet.

The hamster suprachiasmatic nucleus (SCN) is innervated by a dense plexus of enkephalin-containing axons originating from cells in the intergeniculate leaflet (IGL) of the thalamus. However, the distribution of opioid receptors within the hamster SCN has not been reported. Opioid receptors consist of three primary subtypes: mu, delta and kappa opioid receptors. Enkephalins have the highest affinity for delta opioid receptors. Therefore, in the present study, we examined the distribution of delta opioid receptor immunoreactivity in the hamster SCN and the IGL of the thalamus. Coronal sections of the hamster hypothalamus inclusive of the SCN or thalamic regions containing the IGL were prepared at specific times of the day and labeled with anti-delta opioid receptor polyclonal antisera using standard immunohistochemical techniques. delta opioid receptors were heavily distributed within rostral-caudal regions of the SCN, with the densest labeling located in the ventral and medial regions of the mid-SCN. Similar patterns of labeling were observed for tissue prepared during mid-day or mid-night times. In contrast, delta opioid receptor immunoreactivity only sparsely labeled cells in the IGL. Cellular staining in all regions appeared as dark punctate labeling surrounding cells, indicative of terminal boutons. Therefore, it is suggested that delta opioid receptors are located presynaptically on axon terminals within the hamster SCN and IGL. These results suggest that delta opioid receptors may play a role in modulating circadian rhythms generated within the SCN, possibly by regulating transmitter release within the nucleus.