neuropeptide-y and norbinaltorphimine

Stress and anxiety are mainly regulated by amygdala and hypothalamic circuitries involving several neurotransmitter systems and providing physiological responses to peripheral organs via the hypothalamic-pituitary-adrenal axis and other pathways. The role of endogenous opioid peptides in this process is largely unknown. Here we show for the first time that anxiolytic parameters of explorative behavior in mice lacking prodynorphin were increased 2-4-fold in the open field, the elevated plus maze and the light-dark test. Consistent with this, treatment of wild-type mice with selective kappa-opioid receptor antagonists GNTI or norbinaltorphimine showed the same effects. Furthermore, treatment of prodynorphin knockout animals with U-50488H, a selective kappa-opioid receptor agonist, fully reversed their anxiolytic phenotype. These behavioral data are supported by an approximal 30% reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus and central amygdala and an accompanying 30-40% decrease in corticosterone serum levels in prodynorphin knockout mice. Although stress-induced increases in corticosterone levels were attenuated in prodynorphin knockout mice, they were associated with minor increases in depression-like behavior in the tail suspension and forced swim tests. Taken together, our data suggest a pronounced impact of endogenous prodynorphin-derived peptides on anxiety, but not stress coping ability and that these effects are mediated via kappa-opioid receptors. The delay in the behavioral response to kappa-opioid receptor agonists and antagonist treatment suggests an indirect control level for the action of dynorphin, probably by modulating the expression of CRH or neuropeptide Y, and subsequently influencing behavior.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amygdala; Animals; Anxiety; Brain Stem; Corticosterone; Corticotropin-Releasing Hormone; Dynorphins; Enkephalins; Exploratory Behavior; Female; Guanidines; Hypothalamus; Male; Maze Learning; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphinans; Naltrexone; Neuropeptide Y; Neuropeptides; Protein Precursors; Raphe Nuclei; Receptors, Opioid, kappa; Stress, Psychological

The present study investigated the effect of neuropeptide Y on nociception in the nucleus accumbens of rats. Intra-nucleus accumbens administration of neuropeptide Y induced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats. There were no significant changes in the HWL to both stimulation during 60 min after the administration of NPY to outside of the nucleus accumbens. The anti-nociceptive effect of NPY was blocked by subsequent intra-nucleus accumbens injection of the Y1 receptor antagonist neuropeptide Y 28-36, indicating that Y1 receptor is involved in the neuropeptide Y-induced anti-nociception in the nucleus accumbens. Furthermore, the anti-nociceptive effect of neuropeptide Y was attenuated by intra-nucleus accumbens administration of the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in the neuropeptide Y-induced anti-nociception in the nucleus accumbens of rats. Moreover, the neuropeptide Y-induced anti-nociception was attenuated by following intra-nucleus accumbens injection of the selective opioid antagonists nor-binaltorphimine and beta-funaltrexamine, but not by naltrindole, illustrating that mu- and kappa-opioid receptors, not the delta-opioid receptor, were involved in the neuropeptide Y-induced anti-nociception in the nucleus accumbens of rats.

Topics: Animals; Catheterization; Dose-Response Relationship, Drug; Hot Temperature; Male; Microinjections; Naloxone; Naltrexone; Narcotic Antagonists; Neuropeptide Y; Nucleus Accumbens; Pain Measurement; Peptide Fragments; Physical Stimulation; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Receptors, Opioid

Neuropeptide Y (NPY) and the endogenous kappa-opioid receptor ligand, dynorphin (dyn), stimulate feeding when injected centrally in the rat. Norbinaltorphimine (norBNI, 25 nmol) reduced the feeding response to NPY (2.4 nmol) by 67% (P < 0.02). An additive effect of dynorphin and NPY was seen on food intake (saline 0.8 +/- 0.1, dyn 1.9 +/- 0.4, NPY 6.1 +/- 1.4, dyn and NPY 9.7 +/- 2.2). A component of NPY-induced feeding may be mediated by kappa-opioid neuronal systems.

Topics: Animals; Cerebral Ventricles; Drug Administration Schedule; Dynorphins; Feeding Behavior; Injections, Intraventricular; Male; Naltrexone; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Opioid, kappa

A marked increase in food intake is observed in the rat after central injection of neuropeptide-Y (NPY), dynorphin, or noradrenaline (NA). Levels of both NPY and dynorphin are increased in the hypothalamus of food-deprived rats. The aim of this study was to explore the role of NPY, dynorphin, and NA in the central control of feeding after a period of food deprivation. We have investigated the effect of intracerebroventricular injection of a monoclonal antibody to NPY (NPYAb), a potent and selective kappa-opioid receptor antagonist norbinaltorphimine (norBNI), and the alpha-adrenergic antagonist phentolamine on fast-induced food intake. In animals provided with food after a 24-h fast, NPYAb given 10 min before presentation of food reduced food intake by 30% (P < 0.01) compared to that of animals pretreated with an antibody to chloroquine. A similar (34%; P < 0.05) reduction in fast-induced feeding occurred after pretreatment with norBNI. If norBNI was given together with NPYAb, then a reduction of 51% (P < 0.05) was observed. Pretreatment with phentolamine reduced fast-induced food intake by 39% (P < 0.05), with no evidence of an additive effect when phentolamine was given together with NPYAb. These data would support a role for endogenous NPY, dynorphin, and NA in the mediation of fast-induced feeding. NPY would seem to act independently of dynorphin, but through the same mechanism as NA.

Topics: Animals; Antibodies, Monoclonal; Dynorphins; Eating; Food Deprivation; Immunization, Passive; Male; Naltrexone; Neuropeptide Y; Norepinephrine; Phentolamine; Rats; Rats, Wistar; Receptors, Opioid, kappa

The non-selective opioid receptor antagonist naloxone decreases the robust feeding observed after i.c.v. injection of neuropeptide Y (NPY). In the present study we evaluated the effects of three selective opioid receptor antagonists on NPY-induced feeding. Graded doses of norbinaltorphimine (norBNI), beta-funaltrexamine (beta-FNA) and naltrindole (NTI), antagonists of the kappa, mu and delta receptors respectively, were preinjected (i.c.v.) in male rats prior to injection of 5 micrograms NPY (i.c.v.). Food intake was measured 1, 2 and 4 h post-NPY injection. Injection of beta-FNA and norBNI were most effective in reducing NPY-induced feeding, whereas NTI had little effect on NPY-induced feeding.

Topics: Animals; Eating; Injections, Intraventricular; Male; Naltrexone; Narcotic Antagonists; Neuropeptide Y; Rats; Rats, Sprague-Dawley