Ablation of pituitary pro-opiomelanocortin (POMC) cells produces alterations in hypothalamic POMC mRNA levels and midbrain mu opioid receptor bindingin a conditional transgenic mouse model
Y. Zhou et al., Ablation of pituitary pro-opiomelanocortin (POMC) cells produces alterations in hypothalamic POMC mRNA levels and midbrain mu opioid receptor bindingin a conditional transgenic mouse model, J NEUROENDO, 13(9), 2001, pp. 808-817
The hypothalamic-pituitary-adrenal (HPA) axis is regulated by stress-relate
d excitatory inputs, and various inhibitory and negative-feedback controls
by glucocorticoids and opioids, including pro-opiomelanocortin (POMC)-deriv
ed peptides. The role of POMC-derived peptides of pituitary origin in the m
odulation of brain POMC mRNA expression and opioid receptor binding was inv
estigated using a line of transgenic mice that express a fusion gene compos
ed of the pituitary expression-specific promoter region of the POMC gene dr
iving the herpes simplex viral-1 thymidine kinase (TK). Male adult mice wer
e treated with the antiherpes agent ganciclovir that selectively ablates ce
lls expressing TK. Following treatment, POMC mRNA levels, measured by quant
itative solution hybridization/RNase protection assays, were decreased by 4
8% in the pituitary of the TK+/+ mice, reflecting an expected loss of the p
ituitary corticotrope POMC cells. This treatment also significantly lowered
pituitary beta -endorphin immunoreactivity content and plasma concentratio
ns of corticosterone. In contrast, POMC mRNA levels were increased by 79% i
n the hypothalamus of the TK+/+ mice with pituitary POMC cell ablation. Bin
ding of [H-3]DAMGO to mu opioid receptors, as measured by quantitative auto
radiography, was significantly reduced in several brain regions including t
he central grey, median raphe and superficial grey layer of the superior co
lliculus. These regions are innervated by hypothalamic POMC neurones. No si
gnificant differences in binding to either kappa or delta opioid receptors
were found in the brain regions studied. These results suggest that POMC-de
rived peptides of pituitary origin may exert a tonic negative-feedback effe
ct on hypothalamic POMC neurones. In turn, the downregulation of central mu
opioid receptors in this model may be mediated through a mechanism related
to hypothalamic POMC overexpression.