Elevated glucocorticoid levels are responsible for induction of tyrosine hydroxylase mRNA expression, phosphorylation, and enzyme activity in the nucleus of the solitary tract during morphine withdrawal.
Chronic opiate exposure induces neurochemical adaptations in the noradrenergic system. Enhanced responsiveness of the hypothalamo-pituitary-adrenal axis after morphine withdrawal has been associated with hyperactivity of ascending noradrenergic input from the nucleus of the solitary tract (NTS-A(2)) cell group to the hypothalamic paraventricular nucleus (PVN). This study addressed the role of morphine withdrawal-induced corticosterone (CORT) release in regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis in adrenalectomized (ADX) rats supplemented with low CORT pellet (ADX plus CORT). Present results show that in sham-ADX rats, noradrenergic neurons in the NTS-A(2) became activated during morphine withdrawal, as indicated by increased TH mRNA expression. However, this induction of TH expression is not detected in ADX plus CORT rats that are unable to mount CORT secretory response to morphine withdrawal. Total TH protein levels were elevated in the NTS-A(2) from sham-operated rats during morphine dependence and withdrawal, whereas we did not find any alteration in ADX plus CORT animals. Furthermore, high levels of TH phosphorylated (activated) at Ser31 (but not at Ser40) were found in the A(2) area from sham-morphine withdrawn rats. Consistent with these effects, we observed an increase in the enzyme activity of TH in the PVN. However, induction of morphine withdrawal to ADX plus CORT animals did not alter the phosphorylation (activation) of TH in NTS-A(2) and decreased TH activity in the PVN. These results suggest the existence of a positive reverberating circle in which elevated glucocorticoids during morphine abstinence play a permissive role in morphine withdrawal-induced activation of noradrenergic pathway innervating the PVN.
Núñez
Cristina
C
Department of Pharmacology, University School of Medicine, Campus de Espinardo, 30100 Murcia, Spain.
Földes
Anna
A
Pérez-Flores
Domingo
D
García-Borrón
J Carlos
JC
Laorden
M Luisa
ML
Kovács
Krisztina J
KJ
Milanés
M Victoria
MV
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000378:metabolism*; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000503:physiopathology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D015431:Weight Loss / Q000187:drug effects
D012333:RNA, Messenger; D009020:Morphine; D000324:Adrenocorticotropic Hormone; D014446:Tyrosine 3-Monooxygenase; D003345:Corticosterone; D006854:Hydrocortisone