Daily morphine injection and withdrawal disrupt 24-h wheel running and PERIOD2 expression patterns in the rat limbic forebrain

Symptoms of opiate withdrawal include disturbances in circadian rhythms. We examined in male Wistar rats (n=48) the effects of a daily, mid-morning morphine injection (5–40 mg/kg, i.p.) and its withdrawal on 24-h wheel-running activity and on the expression of the clock protein, PERIOD2 (PER2), in the suprachiasmatic nucleus (SCN), oval nucleus of the bed nucleus of the stria terminalis (BNSTov), central amygdala (CEA), and dorsal striatum. Rats were killed over 2 days at 10, 22, 46, and 58 h after the last daily morphine injection at zeitgeber times (ZT) 1 or ZT13. Daily morphine injections and their withdrawal suppressed nighttime wheel running, but did not entrain any increase in activity in advance of the injection. Neither morphine injection nor its withdrawal affected PER2 expression in the SCN, whereas the normal daily peaks of PER2 in the BNSTov, CEA, and dorsal striatum were blunted both during morphine administration and its withdrawal. Treatment with a dopaminergic agonist (the D2/3 agonist, quinpirole, 1.0 mg/kg) or a noradrenergic agonist (alpha2 agonist, clonidine, 0.1 mg/kg) in morphine withdrawal did not restore normal PER2 patterns in each affected region; however, both quinpirole and clonidine themselves altered normal daily PER2 expression patterns in morphine-naive rats. These findings confirm and extend previous observations that opiates disrupt daily patterns of clock gene expression in the limbic forebrain. Furthermore, catecholaminergic drugs, which have been previously found to alleviate symptoms of opiate withdrawal, do not alleviate the effects of morphine withdrawal on PER2, but do modulate daily patterns of PER2 expression in saline controls.

▶Daily mid-morning morphine injections suppress nighttime wheel running in rats. ▶Morphine injections reduce peak expression of PERIOD2 in limbic forebrain regions. ▶Peak PER2 expression remains reduced in these regions after morphine withdrawal. ▶The D2 agonist, quinpirole, increases PER2 in BNSTov and CEA in withdrawal. ▶The alpha2 adrenergic agonist, clonidine, increases PER2 in striatum in withdrawal.