The Neuroendocrine Paraventricular Hypothalamus: Receptors, Signal Transduction, mRNA and Neurosecretion
Authors: Lightman Stafford L. 
Published: April 2021

The hypothalamus is one of the most studied areas of the central nervous system. Many of its functions are understood and there is an extensive literature on its role in the control of pituitary hormone secretion, autonomic nervous system activity, regulation of salt, water and food ingestion, body temperature regulation and aspects of behaviour. Although the role of the hypothalamus in the control of pituitary secretion was postulated in the early 1900s, the chemical nature of these control mechanisms has only been documented in the last few years.

The opioid peptides represent one particular family of chemical compounds which have been shown to have many effects on pituitary hormone secretion. Exogenous opioids inhibit the neurosecretion of both vasopressin and oxytocin from the posterior pituitary neurosecretory terminals of hypothalamic cell bodies. Opioids also have major actions on the secretory activity of the anterior pituitary which has no innervation from the hypothalamus, but which is regulated by blood borne factors in the hypophyseal portal circulation which runs from the median eminence of the hypothalamus. It was therefore of considerable interest when it was discovered that endogenous opioid peptides could be detected both in the neurohypophyseal system and in cells which project into the median eminence.

The simple presence of a peptide in a neurone does not necessarily imply a function. If, however, we can demonstrate that regulation of the synthesis of the peptide occurs in a manner which corresponds with the expected role of the agent, this provides powerful data in support of a genuine physiological function. The elucidation of the genomic structure of the precursors for the three endogenous opioid peptides has provided us with the ability to measure mRNA for these peptides in defined areas of the brain and to assess their response to appropriate stimuli. Not only does mRNA for the endogenous opioid dynorphin coexist in the same cells as vasopressin but we have now been able to demonstrate that stimuli to vasopressin secretion also result in a markedly increased accumulation of dynorphin mRNA. Similarly, previous studies have shown that opioid peptides derived from another precursor - pro-enkephalin A - coexist with corticotrophin releasing factor in a different group of hypothalamic cells. We have now been able to demonstrate that stresses which result in an accumulation of corticotrophin releasing factor mRNA also result in increased pro-enkephalin mRNA in the same area. This considerably strengthens the hypothesis that endogenous opioids do play a significant role in the control of hypophyseal secretion.

The ability to perform quantitative assessments of mRNA in anatomically localized areas of the central nervous system can be applied to mRNA for other products of gene transcription including the mRNA for receptors. Acetylcholine is a classic neurotransmitter which has long been known to stimulate the release of vasopressin. A probe complementary to part of the rat nicotinic receptor sequence was found to hybridize to the vasopressin-containing areas of the hypothalamus which project to the neurohypophysis, and indeed the expression of this mRNA could be increased by a stimulus to vasopressin secretion.

Quantitative studies of mRNA should provide a powerful tool for investigating the control of transmitter and receptor physiology at any site in the body which responds to its local chemical environment.