Derivatives of beta-casomorphins with high analgesic potency.

Beta-casomorphin (5) Tyr-Pro-Phe-Pro-Gly, a partial sequence of bovine beta-casein with moderate opioid properties and mu-receptor affinity, was modified by substituting for the natural L-amino acids their D-analogs, and D-pipecolic acid, as well as by amidation of the C-terminal. Substitution of D-Pro or D-pipecolic acid for L-Pro4 considerably increased the analgesic action and the potency on guinea-pig ileum of beta-casomorphin (5) as well as of casomorphin [4] amide. The resulting D-Pro4 analogs Deprolorphin and Deproceptin which showed high analgesic potency after both intracerebroventricular and intravenous administrations. Also, the substitution of D-Phe for L-Phe3 enhanced, even though to a lesser degree, the antinociceptive action. Both naltrexone and naloxone completely blocked the effects in vivo and in vitro. The substitution of D-Pro for L-Pro2 abolished the opioid-like actions, while substituting D-pipecolic acid for L-Pro2 resulted in an increased analgesic effect of remarkably long duration. The correlation of analgesic action with the effects on isolated organs separates the L-Pro4-substituted derivatives and D-Phe3-CM(5) from the other modified casomorphins and morphine, indicating that the analgesic potency of the former was about ten times that of the latter group in the case of identical GPI-potency. This may involve different subpopulations of opiate mu-receptors.

Avoidance and brightness discrimination conditioning in genetically different lines of rats.

Rats from an albino stock were selected for high (HAS) and low (LAS) avoidance scores measured in a shuttle-box. Learning performance of male rats was compared in three different tests: the shuttle-box, the pole jumping-box, and the Y-chamber. It was shown that rats of the HAS line more rapidly acquired conditioned avoidance in the shuttle-box experiment and the pole-jumping experiment than LAS, whereas we could not detect any significant differences in brightness discrimination. In the open field test rats of the HAS line were more active in comparison to LAS's, measured in terms of higher ambulation scores. In conclusion, it is verified that the shuttle-box performance as well as pole-jumping performance is highly determined by the emotional status of the animals and, moreover, that avoidance learning is based on mechanisms other than brightness discrimination learning.

Pharmacological effects on two inbred substrains of AB mice.

Mice of the two substrains AB/Gat and AB/Hal from the Jena AB inbred strain differ in behavior from each other by their aggressiveness occurring especially in the latter group after maturity. In order to ascertain the neurobiological background of aggressiveness, we injected mice of both substrains with either haloperidol, diazepam, or hexobarbital and measured their response on motor activity. In a second experiment, the reaction to a seizure evoking agent (pentylenetetrazol) was determined. Mice of both substrains were found to differ significantly in their reaction to haloperidol or diazepam injection. In contrast to that no changes in motor activity could be detected following hexobarbital administration. Animals of the aggressive AB/Hal substrain reacted more pronounced to pentylenetetrazol than those of the AB/Gat group. In conclusion, the varying aggressiveness of both AB mice substrains may be due to differences in dopaminergic and GABAergic neurotransmission.