V. A. Dubynin

Effects of Peptide and Non-Peptide Opioids on Protective Reaction of the Cockroach Periplaneta americana in the “Hot Camera”

The ability of morphine, naloxone, and several opioid peptides of the group of beta-casomorphines to change the time of the stay of cockroaches Periplaneta americana in a hot camera (t = 47°C) was studied. It has been shown that the morphine dose ED50 increasing twice the stay amounts to 200 µg/g, while hat of naloxone, to 40, of heptapeptide YPFPGPI, to 440, and of pentapeptide YPFPG, to 420 µg/g. Hexapeptide YPFPGP free of the N-terminal tyrosine had no statistically significant effect on the stay duration. The earlier changes of the stay duration (in 15–60 min after injection; the most pronounced for morphine and naloxone) corresponded to the ability of these drugs to act on the mu-type opioid receptors. The high peptide affinity to the delta-type receptors led to development of the later effects (in 90–150 min after injection; the most pronounced for heptapeptide YPFPGPI). A combined injection of naloxone and heptapeptide lead to the mutual inhibition of their effect: the peptide eliminated the early effect of naloxone on the stay duration, whereas naloxone, the late effects of beta-casomorphine. The obtained results indicate an important role of the endogenous opioid system in control of protective behavior of insects, as well as heterogeneity of the receptor components of the system.

Delayed behavioral effects of β-casomorphin-7 depend on age and gender of albino rat pups

Systemic administration of β-casein heptapeptide β-casomorphin-7 (YPFPGPI, 1 mg/kg daily) to 10–23-day-old albino rat pups produced delayed anxiolytic effects, which were more pronounced in female than in male rats. Experimental findings confirm our assumption on the important role of nutritional opioids in brain development in newborn mammals.Systemic administration of β-casein heptapeptide β-casomorphin-7 (YPFPGPI, 1 mg/kg daily) to 10–23-day-old albino rat pups produced delayed anxiolytic effects, which were more pronounced in female than in male rats. Experimental findings confirm our assumption on the important role of nutritional opioids in brain development in newborn mammals.

Effects of Several Exorphins and Endorphins on the Escape Reaction of the Cockroach Periplaneta americana under Elevated Temperature Conditions

The ability of several alimentary opioid peptides (exorphin C, rubiscolin-5, cytochrophin4) and endorphins (met-enkephalin, dinotrophin A1−10, β-neoendorphin) to change the escape reaction of the cockroaches Periplaneta americana at their placement into a hot chamber was studied. The ED50 values increasing twice the insect stay time in the hot chamber as well as duration and dynamics of the effects were determined. It has been shown that ED50 decreases statistically significantly with increase of the length of the peptide molecule and its affinity to opioid receptors of the κ-type. Selective binding of opioid to μ-receptors leads to a decrease of duration of the effects and to an increase of their affinity to δ-receptors—to prolongation of the reaction (more than 150 min). In the group of alimentary peptides (exorphins) the most active was a fragment of D-ribulose-1,5-biphosphate carboxylase/oxigenase rubiscolin-5 (ED50 = 386 nM per individual). This might indicate a specific ability of some plant proteins to regulate (decrease) the insect protective behavior.

Comparative analysis of neurotropic activity of exorphines, derivatives of dietary proteins

The effects of wheat gluten fragments, hemoglobin, and milk β-caseins (exorphine C, hemorphine-6, and β-casomorphine-7) on nociceptive sensitivity and behavior were studied in albino rats. Hemorphine-6 and exorphine C induced hyperalgesia and increased anxiety; β-casomorphine-7 decreased anxiety and nociceptive sensitivity. All peptides partially decreased motor activity and the orientative-exploring reaction. In contrast to β-casomorphine-7, exorphine C and hemorphine-6 did not exhibit neurotropic activity intrinsic to opioids and can be characterized as functional antagonists of endogenous opioid peptides.

Role of the Brain Dopaminergic and Opioid System in the Regulation of “Child’s” (Maternal Bonding) Behavior of Newborn Albino Rats

Administration of D2 receptor antagonist clebopride in a dose not affecting locomotor activity was followed by a decrease in maternal bonding behavior of 10-day-old and 15-day-old albino rat pups. D1 receptor antagonist SCH23390 had a stimulatory effect only on the behavior of 10-day-old newborns. Opioid peptide β-casomorphin-7 abolished the effect of clebopride in rat pups of the older age group.

Delayed effect of exorphins on learning of albino rat pups

The delayed effect of food-derived opioid peptides (exorphins) after chronic administration on postnatal days 1–14 on the learning of albino rat pups has been studied. Heptapeptide YPFPGPI (β-casomorphin-7), pentapeptide YPLDL (rubiscolin-5) and pentapeptide YPISL (exorphin C) improved the development of the conditioned foraging reflex in a complex maze. Hexapeptide PFPGPI lacking the N-terminal tyrosine proved inefficient. Only β-casomorphin-7 had an effect (negative) on passive avoidance conditioning. The obtained data confirm that exorphins (particularly, milk-derived β-casomorphins) can have significant and long-term effects on the environmental adaptation of young mammals.

Activation of maternal behavior of albino rats after combined treatment with dopamine and opioid receptor antagonists in low doses

We studied the effect of D1/D2 antagonist haloperidol on maternal motivation in nursing albino rats. Haloperidol in a dose of 0.2 mg/kg significantly attenuated parental reactions and motor and exploratory activities. In a lower dose (0.1 mg/kg) the drug produced the same effect on maternal behavior (number of approaches to newborns) without reducing motor activity. The effect of low-dose haloperidol was different after naloxone treatment (0.2 mg/kg intranasally): the number of pup transfers increased significantly. The detected phenomenon indicates good prospects of combined treatment with agents modifying the cerebral dopaminergic and opioid systems as the method for correction of disorders in maternal behavior.

Effect of Opioid Antagonist Naloxone on Maternal Motivation in Albino Rats

We studied the effect of nonselective antagonist of opioid receptor naloxone on the behavior of albino female rats on days 4–6 after delivery. Intraperitoneal injection of naloxone (5 mg/kg) significantly stimulated maternal reactions (increased the number of approaches to pups, decreased the latency of their transfer into new location). Intranasal naloxone (1 mg/kg) produced similar changes. Naloxone in intraperitoneal dose of 1 mg/kg and intranasal dose of 0.2 mg/kg virtually did not modify maternal behavior.

The effect of FMRFa-like peptides on rats reanimated after clinical death

The effects of the endogenous, paraopioid FMRFa and FMRFa-like peptides are compared upon reanimation of rats after clinical death caused by acute hemorrhage. It is found that FMRFa restores cardiohemodynamics and respiratory function more effectively than RFa and RF×2HCl. The nonpeptide opioid antagonist naloxone does not alleviate the effects of acute hernorrhage. It is assumed that the reanimating effect of the studied peptides is realized via mechanisms that are not associated with opiates.

Behavioral Effects of Original Tetrapeptide, an Analog of N-Terminal Nociceptin Fragment

The study examined the effect of an analog to N-terminal nociceptin fragment AcOH × Phe-Gly-Gly-Phe-NH2 on the behavior of albino rats. This tetrapeptide (5 μg/kg intraperitoneally) signifi cantly enhanced motor and exploratory activity in mature rats and in 42-day pups and produced opposite effects in 21-day rat pups, which attests to the complex dynamics of maturation of nervous structures involved in the realization of nociceptin action.