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The Prader-Willi syndrome is a human disease whose physiological causes have not yet been elucidated. However, clinical and biological parameters suggest that it is an hypothalamic disorder. This syndrome is the most common form of human congenital obesity. In many cases, the genetic alteration has been identified as a microdeletion in the chromosomal region 15q11-q13. Consequently, one can presume that obesity in patients with Prader-Willi syndrome is the result of some hypothalamic deficiency involving the products of one or several genes found in this region of chromosome 15. Several DNA markers belonging to this genomic region have been isolated. If these are fragments of expressed genes, it may be possible to examine the possible association of their products with the hypothalamus and the disease. Such studies may provide new insights into the role of the hypothalamus in the pathophysiology of obesity.

Immunoreactivity to the secretory protein 7B2 (IR-7B2) colocalizes with both AVP and Om in separate groups of neurons in the supraoptic nucleus. In mutant Brattleboro rats, which have aberrant AVP, which results in diabetes insipidus, 7B2 appears to be markedly decreased in vasopressinergic neurons and absent in their corresponding neurohypophyseal terminals. In contrast, no dramatic differences could be observed in oxytonergic somatas and fibers.

The biosynthesis of numerous polypeptide hormones implicates two types of precursors: pre- and prohormones. The structure, characteristics, and role of these hormone precursors is discussed taking as examples parathyroid hormone and insulin. After this general introduction, the case of the common precursor for adrenocorticotropin and beta-lipotropin is then discussed. Its maturation proceeds through a serie of proteolytic steps which lead to the formation of various end products characterized each by a biological activity of its own.

The knowledge of the amino acid sequence of both beta-lipotropin (beta-LPH) and gamma-LPH was the starting point that led to the hypothesis, considered revolutionary in 1967, that hormonal precursors exist. This concept was simultaneously proposed for proinsulin and applied later to other polypeptide hormones. The discovery of endorphins brought together two fields of research that were not related: the opiates and the so-called pituitary lipotropic hormones. The demonstration of specific brain opiate receptors led to the hypothesis of the existence of endogenous opiate ligands which could act as neurotransmittors. The isolation of such substances in the brain, first named enkephalins, revealed through their amino acid sequence their structural homology with the pituitary lipolytic hormones. The finding of a more potent opioid substance in the pituitary (beta-endorphin) that comprises the last 31 amino acids of beta-LPH shed a new light on the hypothesis proposed earlier which gave to beta-LPH a role as a precursor molecule. Finally, the addition of ACTH completed a putative multipotent precursor model that has been recently named pro-opiomelanocortin. Pulse-chase experiments have definitely proven that beta-endorphin is a maturation product of a large precursor also containing ACTH and MSH. In other studies, many groups have suggested that endorphins play important roles as possible neuromodulators in pain transmission, in analgesia, in tolerance and dependence, as well as on behavior and endocrine regulations, mainly those related to the hypothalamo-pituitary axes. The elucidation of the biosynthetic process or processes of cerebral endorphins (either enkephalins or beta-endorphin) is of primary importance in order ot understand better their biological as well as regulatory functions. These studies should also be applicable to the biosynthesis of all the other neuronal peptide hormones. It is hoped that they will provide new tools for the study of some important central nervous system functions, such as pain and endocrine control and the physiopathology of behavioral diseases.

We have recently developed methods to identify biosynthetized beta-endorphin and beta-lipotropin (beta-LPH) following incubation of Rat pars intermedia with radioactive amino acids. We used the same approach for rat brain tissue. In the striatum we found a peptide similar to beta-LPH while its identification in hypothalamus was less positive. This is the first demonstration of such biosynthesis and it could well be an important step in determining the biosynthetic patterns of cerebral endorphins and enkephalins.

We have demonstrated that beta-lipotropin is a precursor molecule and that during its maturation, it gives rise to beta-endorphin. This model is similar to proinsulin, proparathyroid hormone and proglucagon models. Since beta-endorphin is also found in the hypothalamus, one can foresee that its biosynthesis will be similar if not identical. It is then conceivable to believe that the other hypothalamic factors are issued from larger precursor molecules. When this will be shown, and well established, studies on their control mechanism will be much easier.

Endorphins represent a family of brain peptides having an opioid core structure responsible for their morphinomimetic activity. We present an overview of the biology of endorphins including their origin, neuroanatomical distribution, regulatory mechanisms and interaction with opioid receptors taking neuronal cellular function in situ as our focal point of interest. Differential biochemical processing and regulatory mechanisms both at the pre- and post-translational level in the various brain areas contribute to the biochemical and functional diversity of peptides generated from common precursors in keeping with the selective needs and functions of neuronal circuits. Physiological significance requires interaction of the various endogenous ligands thus generated with appropriate receptors, sometimes located well beyond the distance of a synaptic cleft as demonstrated by the diverging ligand/receptors neurochemical topographical maps. Physiological analysis reveals a multitude of potential interactions between peptides and classical neurotransmitters in part as a result of their common subcellular location within individual synaptic vesicles but also in relation to qualitatively different post-synaptic effects and metabolism, enhancing the complexity of their potential role in neuronal function. Endorphins may contribute to major neuroendocrine systems such as analgesia, endocrine and autonomic function, mental function and behavior. Their implication in various neuropsychiatric and endocrine clinical disorders will be briefly reviewed.