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Human MPF (Lys-Lys-Gly-Glu) stimulates the proliferative response of human lymphocytes to the T-cell mitogen concanavalin A by 121-751% in the concentration range 10(-11)-10(-4) M; the peak effect is at 10(-8) M, lower or higher concentrations eliciting reduced responses, i.e. the dose-response curve is bell-shaped. Species specificity is high. Human MPF similarly stimulates rat lymphocytes, but the peak effect is seen at a 100-fold higher dose (10(-6) M). Rat MPF (Lys-Lys-Gly-Gln) has a peak effect at 10(-6) M with human lymphocytes, but the peak effect with rat lymphocytes is at a 1000-fold lower dose (10(-9) M). Truncated forms of the MPFs (Gly-Glu, Gly-Gln, Gly, Glu, Gln) and opioid peptides (beta-endorphin, [Leu] and [Met]enkephalin) show insignificant or only weak stimulatory or inhibitory effects. These results suggest that MPF acts via specific non-opioid receptors located on lymphocytes and that endogenously released MPF may have an important role in the functioning of the immune system.

MPF is a tetrapeptide (structure Lys-Lys-Gly-Glu) that elicits a variety of neurotrophic effects in vivo consistent with a role in neuronal regeneration. In support of this role, we now show that MPF stimulates the proliferation of cultured astrocytes and neurite outgrowth from cultures of neocortical cholinergic and mesenchephalic dopaminergic neurons. The dose-response relationships are biphasic ("bell shaped"), maximal responses being obtained with 10(-6) M concentrations of MPF. MPF and nerve growth factor seem to act on different receptors, because their effects on cholinergic neurons are synergistic.

We have previously shown that a metabolically stable analogue of MPF, the C-terminal tetrapeptide of human beta-endorphin of structure Lys-Lys-Gly-Glu, reduces the turning behaviour of rats with unilateral lesions of their nigro-striatal pathways. Transmission electron microscopy (TEM) has now revealed that this effect is related to reversal of the mitochondrial damage to substantia nigra (SN) neurones induced by the lesion. The results are consistent with the concept that an inherited defect in components of the mitochondrial enzyme system is the initial step in the genesis of Parkinson's disease (PD). They also, in conjunction with known neurotropic properties of MPF, and our unpublished finding of high concentrations of an MPF-like peptide in human basal ganglia, suggest that MPF may have physiological significance in the development and regeneration of the human CNS.

A single intrastriatal injection of a slow release formulation of a metabolically-stable MPF analogue was given to rats with lesioned right nigrostriatal pathways. After 6 weeks the turning behaviour of the rats in response to D-amphetamine began to decline, and after 12 weeks the reduction was marked and consistent. The implication of our results in the use of intracerebral grafts in parkinsonian patients is discussed.

An in-vitro perifusion system was devised in order to examine the secretory profiles of isolated islets of Langerhans, derived from different physiological states, when subjected to various stimuli relevant to lactation. Islets from pregnant rats secreted more insulin than did those from virgin animals; however, islets from lactating and virgin animals secreted similar amounts of insulin with all stimuli, including glucose, amino acids, cations and neurotransmitters. When virgin rats were pretreated for 5 days in vivo with GH or prolactin, insulin responses in vitro were unchanged. Cannulation of the hepatic portal vein and inferior vena cava in vivo revealed that both insulin and glucose concentrations were lower in the portal vein of the lactating rat compared with the virgin animal. It was therefore concluded that insulin concentrations are depressed during lactation as a consequence of the pancreas receiving a diminished glycaemic stimulus rather than because of any change in beta-cell sensitivity.

Ergocryptine (2 mg/kg) caused short- and long-term reduction of prolactin secretion in rats experiencing concurrent lactation and pregnancy. The long-term effects of the drug lasted at least 60 days and resulted in reduced milk secretion and termination of pregnancy. Prolactin replacement therapy at a low dose (5 i.u./day) was unsuccessful in overcoming these effects but a higher dose (up to 60 i.u./day) increased milk production and maintained pregnancy. One possible explanation of these results is that prolactin, rather than the suckling stimulus, was responsible for the suppression of oestrous cycles, because ergocryptine brought about a resumption of oestrous vaginal smears in all treated rats in spite of continued suckling.

A highly specific antiserum to rat GH (anti-rGH) was used to assess the role of GH in lactation in the rat. When administered alone, anti-rGH had no effect on litter weight gain, whereas bromocriptine reduced serum prolactin concentrations and litter weight gain for up to 7 days when given on day 4 of lactation. When bromocriptine and anti-rGH were given in combination, however, litter weight gain declined even more dramatically so that pups were receiving virtually no milk 2-3 days after treatment. Daily litter exchange failed to prevent this effect. Concurrent injections of highly purified GH (prolactin contamination undetectable) prevented the dramatic decline in litter weight gain induced by combined bromocriptine and anti-rGH treatment, so that these litters grew as well as those receiving bromocriptine alone. Growth hormone did not act by influencing serum prolactin concentrations, which remained low during GH therapy. Direct effects of anti-rGH or GH on the pups (transferred through the milk) were ruled out since virtually identical results were obtained when milk yield was estimated during a 30-min suckling period after a 3-h separation of mother and pups. Lactation had virtually ceased 3 days after treatment with both bromocriptine and anti-rGH, but it could be reinitiated by a single injection of prolactin or GH, and subsequent recovery was virtually complete. The results of this study show that prolactin can maintain a full milk yield in the absence of GH, milk yield is reduced by approximately 50% in the absence of prolactin and milk yield is totally stopped in the absence of prolactin and GH.(ABSTRACT TRUNCATED AT 250 WORDS)

The seasonal maturation of four species of helminths, Acanthocephalus clavula, A. lucii, Camallanus lacustris and Bunodera luciopercae, from the perch Perca fluviatilis is briefly described. It is noted that A. clavula, A. lucii and C. lacustris are found as mature worms in the intestine of the fish host throughout the year, whereas in Bunodera luciopercae there is a limited season of maturation. As a result of experimental studies it is suggested that B. luciopercae uses host gonadotrophin to initiate and stimulate the early phase of gametogenesis. The gonadotrophin may also activate the parasites' own endocrine system, which then takes over control of subsequent spermatogenesis and oogenesis. This formation is used for a hypothesis for seasonal maturation of helminths in the fish definitive host. It also provides a potential explanation for seasonal maturation of helminths of fish in polar and tropical zones of the world.

The ability of newts and other urolele amphibians to regenerate an accidentally-removed or amputated limb is lost after hypophysectomy, but restored following intraperitoneal injection of beta endorphin, or the C-terminal tetrapeptide sequence of human beta endorphin, Lys-Lys-Gly-Glu (= MPF). The closely related tetrapeptide, Lys-Lys-Gly-Gln (the C-terminal sequence of pig, sheep, and camel beta endorphin), the dipeptide Gly-Glu, the enkephalins, and other N-terminal sequences of beta endorphin (eg gamma endorphin) do not elicit the effect.

Litter removal during lactation led to an increase in serum LH concentration, an effect which was completely reversed by prolactin injections. Lactating rats receiving ergocryptine also showed increased serum LH but not to the extent found during litter removal, suggesting that both prolactin and suckling are important factors in the maintenance of lactational anoestrus. The early implantation induced by removal of the litter from rats concurrently lactating and pregnant was not prevented by prolactin. Implantation occurred early in similar rats with serum prolactin levels reduced by ergocryptine treatment and the effect was reversed by prolactin. However, early implantation led to failure of the pregnancy to reach term. These results show that, although prolactin is involved, the suckling stimulus is also essential to prevent implantation in rats with concurrent lactation and pregnancy.

The pituitary of roach, Rutilus rutilus (L.), is pear-shaped and situated in the sella turcica. It is characterised by a large pars nervosa, which penetrates deep into the other regions, splitting the proximal pars distalis. Spatial localisation of nerve fibre types and glandular cell types occurs. Using a variety of staining techniques six glandular cell types have been localised and their distribution is disucssed in relation to those of the other teleost pituitaries.

The ability of B-endorphin to initiate limb regeneration in hypophysectomised newts is confined to the human species of the peptide and is contained in its C-terminal tetrapeptide sequence, Lys-Lys-Gly-Glu (MPF). Results with fifteen MPF analogs show that: (a) small structural change at the C-terminal Glu residue destroys activity, (b) at the Gly position, change of -NH-CH2-CO by -NH-NH-CO- (Azgly) or -NH-CHMe-CO- (Ala) also destroys the activity, but methylation of the NH results in an analog (Sar) with good activity, (c) analogs in which the Lys residues are replaced by D-Lys, Nle or Orn may retain some activity, particularly when the second Lys is replaced by D-Lys, and (d) the activity is retained or increased by N-terminal acylation. By combining 'favourable' changes, an analog acetyl-Lys-D-Lys-Sar-Glu was devised which was 1.25 times more potent than MPF, and metabolically more stable.

The output of dopamine from cultures of rat adrenal medullary strips was increased by 71-120% when Lys-Lys-Gly-Glu (MPF), the C-terminal tetrapeptide sequence of human beta-endorphin, was added to the culture medium at 100 micrograms/ml concentration. Human beta-endorphin caused a 44% increase, but an N-terminal fragment of its molecule and somatotrophin caused no increase. Results with analogs of MPF show that small structural change of the C-terminal Glu residue causes complete loss of activity.