The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei

Abstract

The suprachiasmatic nuclei (SCN) contain a major circadian pacemaker, which is regulated by photic and nonphotic stimuli. Although enkephalins are present in the SCN, their role in phase regulation of the pacemaker is largely unknown. The opioid agonist fentanyl, a homologue of morphine, is an addictive drug that induces phase shifts of circadian rhythms in hamsters. We observed that these phase shifts are blocked by naloxone, which is a critical test for true opioid receptor involvement, and conclude that opioid receptors are the sole mediators of the actions of fentanyl on the circadian timing system. A strong interaction between opioids and light input was shown by the ability of fentanyl and light to completely block each other's phase shifts of behavioural activity rhythms. Neuronal ensemble recordings in vitro provide first evidence that SCN cells show direct responses to fentanyl and react with a suppression of firing rate. Moreover, we show that fentanyl induces a strong attenuation of light-induced Syrian hamster Period 1 (shPer1) gene expression during the night. During the subjective day, we found no evidence for a role of shPer1 in mediation of fentanyl-induced phase shifts. Based on the present results, however, we cannot exclude the involvement of shPer2. Our data indicate that opioids can strongly modify the photic responsiveness of the circadian pacemaker and may do so via direct effects on SCN electrical activity and regulation of Per genes. This suggests that the pathways regulating addictive behaviour and the circadian clock intersect.

Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus

“…Our data show that morphine applied at ZT7 decreased slightly the spontaneous c-Fos level in the dmSCN, but had no effect on Per genes expression. Likewise, little effect of the μ receptor agonist fentanyl on Per genes expression was reported in hamsters (Vansteensel et al, 2005). Contrary to our expectations, morphine up-regulated pERK1/2 and pGSK3β levels during the day in both parts of the SCN.…”

“…Previous studies have shown that opioids induce phase advance of circadian activity and Per1 expression, decrease spontaneous electrical activity in the SCN and interfere with photic entrainment (Cutler et al, 1999;Tierno et al, 2002;Vansteensel et al, 2005). To investigate the upstream signalling events mediating these actions in the SCN, we tested the effect of morphine on two principal kinases of the circadian clockwork pERK1/2 and pGSK3β, the clock genes Per1 and Per2, and immediate early gene c-Fos.…”

“…Opioids induce phase advance of the circadian system when applied during the day or interfere with photic entrainment when administered at night (Marchant and Mistlberger, 1995;Byku and Gannon, 2000a,b;Meijer et al, 2000;Vansteensel et al, 2005).…”

The effects of buprenorphine on behaviour in the ACI and BN rat inbred strains

“…Recent findings indicate that direct involvement of opioid receptors in altering the electrical activity of the circadian pacemaker and regulation of clock genes. Future experiments will focus on elucidating the subtypes of opioid receptors involved in this regulation and as a consequence, the possible influence of buprenorphine (Vansteensel et al 2005). …”

Orchestration of gene expression and physiology by the circadian clock

“…For example, serotonin receptor agonists phase shift the circadian clock through an increase in cAMP production (Sprouse et al, 2004) and the drug Ecstasy (3,4-methylenedioxymethamphetamine) alters this response (Biello and Dafters, 2001). Similarly, opioids affect the circadian system, suggesting a modulatory role for the clock in pain sensation (Vansteensel et al, 2005).…”