title: Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal.
abstract: In this study, we investigated the effects of acute morphine administration, chronic intermittent escalating-dose morphine administration and spontaneous withdrawal from chronic morphine on mRNA levels of mu opioid receptor (MOP-r), and the opioid peptides pro-opiomelanocortin (POMC) and preprodynorphin (ppDyn) in several key brain regions of the rat, associated with drug reward and motivated behaviors: lateral hypothalamus (lat.hyp), nucleus accumbens (NAc) core, amygdala, and caudate-putamen (CPu). There was no effect on MOP-r mRNA levels in these brain regions 30 min after either a single injection of morphine (10 mg/kg, i.p.) or chronic intermittent escalating-dose morphine (from 7.5 mg/kg per day on day 1 up to 120 mg/kg per day on day 10). Activation of the stress-responsive hypothalamic-pituitary-adrenal axis by 12 h withdrawal from chronic morphine was confirmed; both POMC mRNA levels in the anterior pituitary and plasma adrenocorticotropic hormone levels were significantly elevated. Under this withdrawal-related stress condition, there was an increase in MOP-r mRNA levels in the lat.hyp, NAc core, and CPu. Recent studies have demonstrated a novel role for the lat.hyp orexin (or hypocretin) activation in both drug-related positive rewarding, and withdrawal effects. Around 50% of lat.hyp orexin neurons express MOP-r. Therefore, we also examined the levels of lat.hyp orexin mRNA, and found them increased in morphine withdrawal, whereas there was no change in levels of the lat.hyp ppDyn mRNA, a gene coexpressed with the lat.hyp orexin. Our results show that there is an increase in MOP-r gene expression in a region-specific manner during morphine withdrawal, and support the hypothesis that increased lat.hyp orexin activity plays a role in morphine-withdrawal-related behaviors.
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jacob
authors.initials: J
authors.lastname: Bendor
authors.forename: Lauren
authors.initials: L
authors.lastname: Hofmann
authors.forename: Matthew
authors.initials: M
authors.lastname: Randesi
authors.forename: Ann
authors.initials: A
authors.lastname: Ho
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D015870:Gene Expression; D007026:Hypothalamic Area, Lateral / Q000737:chemistry* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009020:Morphine / Q000009:adverse effects* / Q000494:pharmacology; D017072:Neostriatum / Q000737:chemistry* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics*; D000068797:Orexins; D010903:Pituitary Gland, Anterior / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011916:Rats, Inbred F344; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D000099052:CRF Receptor, Type 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D017450:Receptors, Opioid, mu; D013739:Testosterone; D000099052:CRF Receptor, Type 1; D009020:Morphine; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone