Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

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Prolactin: Structure, Function, and Regulation of Secretion

The endogenous morphinomimetic brain peptides Met5-enkephalin and alpha-, beta-, and gamma-endorphins have been evaluated in rats after intracerebrospinal fluid injection. beta-Endorphin produces marked, prolonged muscular rigidity and immobility similar to a catatonic state, counteracted by the opiate antagonist naloxone; this effect occurs at molar doses 1/100 to 1/400 that at which the other peptides or morphine block the response to painful stimuli. All peptides evoked dose-related, naloxone-reversible, wet-dog shakes in rats that had not been exposed to drugs. beta-Endorphin produced hypothermia, whereas gamma-endorphin produced hyperthermia. Such potent and divergent responses to naturally occurring subtances suggest that alterations in their homeostatic regulation could have etiological significance in mental illness.

https://science.sciencemag.org/content/sci/194/4265/630.full.pdf

Endorphins: profound behavioral effects in rats suggest new etiological factors in mental illness.

The distribution of immunoreactive enkephalin in rat brain and spinal cord was studied by immunoperoxidase staining using antiserum to leucine-enkephalin ([Leu5]-enkephalin) or methionine-enkephalin ([Met5]-enkephalin). Immunoreactive staining for both enkephalins was similarly observed in nerve fibers, terminals and cell bodies in many regions of the central nervous system. Staining of perikarya was detected in hypophysectomized rats or colchicine pretretated rats. The regions of localization for enkephalin fibers and terminals include in the forebrain: lateral septum, central nucleus of the amygdala, area CA2 of the hippocampus, certain regions of the cortex, corpus striatum, bed nucleus of the stria terminalis, hypothalamus including median eminence, thalamus and subthalamus; in the midbrain: nucleus interpeduncularis, periaqueductal gray and reticular formation; in the hind brain: nucleus parabrachialis, locus ceruleus, nuclei raphes, nucleus cochlearis, nuclear tractus solitarii, nucleus spinalis nervi trigemini, motor nuclei of certain cranial nerves, nucleus commissuralis and formatio reticularis; and in the spinal cord the substantia gelatinosa. In contrast enkephalin cell bodies appear sparsely distributed in the telencephalon, diencephelon, mensencephalon and rhombencephalon. The results of the histochemical staining show that certain structures which positively stain for enkephalin closely correspond to the distribution of opiate receptors in the brain and thus support the concept that the endogenous opiate peptides are involved in the perception of pain and analgesia. The localization of enkephalin in the preoptic-hypothalamic region together with the presence of enkephalin perikarya in the paraventricular and supraoptic nuclei suggest a role of enkephalin in the regulation of neuroendocrine functions.

Immunohistochemical localization of enkephalin in rat brain and spinal cord.

A model of fear and pain is presented in which the two are assumed to activate totally different classes of behavior. Fear, produced by stimuli that are associated with painful events, results in defensive behavior and the inhibition of pain and pain-related behaviors. On the other hand, pain, produced by injurious stimulation, motivates recuperative behaviors that promote healing. In this model injurious stimulation, on the one hand, and the expectation of injurious stimulation, on the other hand, activate entirely different motivational systems which serve entirely different functions. The fear motivation system activates defensive behavior, such as freezing and flight from a frightening situation, and its function is to defend the animal against natural dangers, such as predation. A further effect of fear motivation is to organize the perception of environmental events so as to facilitate the perception of danger and safety. The pain motivation system activates recuperative behaviors, including resting and body-care responses, and its function is to promote the animal's recovery from injury. Pain motivation also selectively facilitates the perception of nociceptive stimulation. Since the two kinds of motivation serve different and competitive functions, it might be expected that they would interact through some kind of mutual inhibition. Recent research is described which indicates that this is the case. The most important connection is the inhibition of pain by fear; fear has the top priority. This inhibition appears to be mediated by an endogenous analgesic mechanism involving the endorphins. The model assumes that fear triggers the endorphin mechanism, thereby inhibiting pain motivation and recuperative behaviors that might compete with effective defensive behavior.

A perceptual-defensive-recuperative model of fear and pain

Inescapable foot shock in rats caused profound analgesia that was antagonized by naloxone or dexamethasone when shock was delivered intermittently for 30 minutes, but not when it was delivered continuously for 3 minutes. Thus, depending only on its temporal characteristics, foot-shock stress appears to activate opioid or nonopioid analgesia mechanisms. Certain forms of stress may act as natural inputs to an endogenous opiate analgesia system.

https://science.sciencemag.org/content/sci/208/4444/623.full.pdf

Opioid and nonopioid mechanisms of stress analgesia

ENKEPHALIN, a natural opiate receptor agonist in brain1–4, has been identified by Hughes et al.5 as a mixture of two pentapeptides : H–Tyr–Gly–Gly–Phe–Met–OH (methionine–enkephalin) and H–Tyr–Gly–Gly–Phe–Leu–OH (leucine–enkephalin). Both peptides mimic the ability of morphine to block electrically evoked contractions of mouse vas deferens and guinea pig ileum, and both inhibit the stereospecific receptor binding of the opiate antagonist 3H-naloxone in brain homogenates5. On the basis of this and other6–8 evidence, it has been proposed2,9,10 that enkephalin receptors may be sites at which morphine-like drugs exert their analgesic actions, and that the enkephalins themselves may be modulators or transmitters in brain systems for pain suppression or analgesia. Consistently with this suggestion, we find that methionine–enkephalin and leucine–enkephalin, when administered through permanently indwelling cannulae in the lateral ventricles of rats, induce a profound analgesia in vivo that is fully reversible by naloxone.

Analgesia induced in vivo by central administration of enkephalin in rat

Enkephalin-stimulated prolactin release.

Carbon-13 nuclear magnetic resonance spectroscopy ( I T nmr) has been possible for some time,l-3 but its development as a useful technique for chemists and biochemists lagged behind that of hydrogen nmr due to problems of technology. The biggest problems have been the low sensitivity, 1% of that of 1H for the same applied magnetic field, and the low natural abundance, 1 % , of the magnetic isotope 13C. This huge antagonistic factor has been overcome by isotopic enrichment, continuous-wave time-averaging using adiabatic fast passage, and proton decoupling with its concomitant nuclear Overhauser enhancement. The biggest step forward, however, was taken with the demonstrated viability of the Fourier transform technique * in nmr and the resultant gain of approximately 100 in the time required to obtain a given signal strength by repetitive averaging. An excellent description of the state of this technique has been given recently.5 The chemical shifts of 1°C are far more sensitive to chemical and conformational effects than are those of hydrogen. This is due to the greater number of valence electrons associated with carbon. Carbon-hydrogen,cr carboncarbon and carbon-phosphorus s, 3 spin-spin couplings have been demonstrated to be sensitive to chemical environment and conformation. The longitudinal relaxation time of carbon, TI, will apparently be a very valuable monitor of the relative mobilities of different regions of a molecule.1n Two recent books cover tge 13C literature up to early 1972.l'~ With this increased sensitivity to substituent and conformational effects,

Carbon‐13 nmr studies of peptide hormones and their components *

Dissociation of somatostatin effects. Peptides inhibiting the release of growth hormone but not glucagon or insulin in rats

13C nuclear magnetic resonance spectroscopy is used to gain information on the flexibility of the backbone in peptide hormones and peptide hormone analogs. 13C spin-lattice relaxation times (T1) were measured on luliberin, the luteinizing-hormone-releasing hormone and des(Gly-NH2)10-luliberin-N-ethylamide in aqueous solution at 25.2 and 67.9 MHz at temperatures of 32°, 40° and 55°C. The 13C spin-lattice relaxation times indicate increased flexibility of the peptide backbone in the immediate environment of glycyl residues in luliberin (<Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) and the hormone analog des(Gly-NH2)10-luliberin-N-ethylamide (<Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-NH-CH2CH3) in aqueous solutions. 13C NMR spectroscopy is shown to be a sensitive technique for monitoring the time-averaged conformational flexibility of peptides in solution. Activation energies (Ea) of about 25 kJ/mol were obtained for rotational reorientation of non-terminal α-carbons in the peptide backbone. Rotation of methyl groups was characterized by an Ea of 9.6 kJ/mol whereas reorientation of the N-terminal pyroglutamyl residue showed an Ea value of 14.6 kJ/mol. The Ea values of individual carbons in the side-chains of prolyl, arginyl and leucyl residues in the peptides were similar to those obtained for the α-carbon of the same amino acid residue in the peptide backbone of the hormones.

The influence of glycyl residues on the flexibility of peptide hormones in solution. A 13C-nuclear-magnetic-resonance study of luteinizing hormone-releasing hormone (luliberin) and its des-glycinamide10 N-ethylamide analog.

Dimitrios Sarantakis

Papers

Analgesia induced in vivo by central administration of enkephalin in rat

Enkephalin-stimulated prolactin release.

Carbon‐13 nmr studies of peptide hormones and their components *

Dissociation of somatostatin effects. Peptides inhibiting the release of growth hormone but not glucagon or insulin in rats

The influence of glycyl residues on the flexibility of peptide hormones in solution. A 13C-nuclear-magnetic-resonance study of luteinizing hormone-releasing hormone (luliberin) and its des-glycinamide10 N-ethylamide analog.