Pharmacological, molecular and neuroanatomical analysis of the role of opioid receptor subtypes and genes in regulatory challenges.

摘要

Increases in food intake following 24 h of food deprivation are reduced by systemic and central administration of general opioid antagonists. Mu-selective antagonists are more effective than kappa-selective antagonists in reducing deprivation-induced intake, whereas delta-selective antagonists are minimally effective. Antisense oligodeoxynucleotide (AS ODN) probes directed against different exons of the mu (MOP), delta (DOP), kappa (KOP) and nociceptin (NOP) opioid receptor genes have been able to differentially alter feeding responses elicited by glucoprivation, lipoprivation and by different opioid peptides and receptor agonists. The dissertation examined whether ventricular administration of AS ODN probes directed against different exons of the opioid receptor genes or against the alpha-subunit of different G-proteins (Gialpha 1, Gialpha2, Gialpha3, Gsalpha, Goalpha, Gqalpha or G x/zalpha) caused changes in deprivation-induced intake in rats. The third study evaluated changes in MOR-1 and MOR-1C immunoreactivity in hypothalamic and extra-hypothalamic sites implicated in feeding behavior, in rats exposed to either food restriction of various durations (2, 7, 14 or 14 days followed by a 7-day recovery period) or food deprivation (24, 48 or 48 h followed by a 7-day recovery period), in addition to an ad libitum group. The fourth study used AS ODN probes directed against exons of the opioid receptor genes in mice, in addition to the general opioid receptor antagonist naltrexone and the selective opioid receptor antagonists betaFNA, NBNI and NTI, in both species. Antisense probes against exons of the MOP gene moderately reduce deprivation-induced intake whereas betaFNA produces great reductions in both rats and mice. MOR-1-LI remained unchanged in rats that were either food-deprived or food-restricted but MOR-1C-LI was significantly increased in the parvocellular PVN following food restriction of 14 days. Thus the data from the studies comprising this dissertation suggest that the regulatory challenge of food deprivation is mediated by all opioid receptors in the mouse and by mu and kappa in the rat. Moreover, the mu receptor antagonist effects seem to be a reflection of effects on MOP splice variants recently identified in the mouse.