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mise à jour du
16 novembre 2008

Influence of modified casomorphins
on yawning behavior of rats
Rüthrich HL, Grecksch G, Matthies H.
Institute of Pharmacology and Toxicology, Medical Academy, Magdeburg


Apomorphine-induced yawning was completely suppressed in animals treated with 5 nmol [D-Pro4]casomorphin (CM) (ICV), 10 nmol [D-Phe3]CM (ICV) or 10 nmol [D-Pip4]CM (ICV). The apomorphine-induced yawning was also decreased, by des-Tyr analogs, but only by about 50%. Physostigmine (0.15 mg/kg, IP) induced yawning. The physostigmine-induced yawning was suppressed by 5 nmol [D-Pro4]CM and 10 nmol [D-Phe3]CM. Both [des-Tyr-D-Phe3]CM and [des-Tyr-D-Pip4]CM were without effect, whereas [des-Tyr-D-Pro4]CM increased significantly the physostigmine-induced yawning. The results suggest that dopaminergic transmission can be modulated by beta-casomorphin derivatives, thus resulting in a decrease in yawning. In the case of the des-tyrosine derivatives, we can assume a dopaminergic modulation, too. An increase in serotonergic activity might be supposed for [des-Tyr-D-Pro4]CM.
B-CASOMORPHIN( l-5) (CM) (Tyr-Pro-Phe-Pro-Gly), a partial sequence of bovine $-casein, exhibits analgesic potency due to a particular affinity to opiate receptors. Modified derivatives have been obtained by substituting D-amino acids, which showed a considerable increase in receptor affinity and an enhanced resistance to enzymatic degradation resulting in an augmented analgesic action.
Further pharmacological studies demonstrated not only antinociceptive properties of these casomorphins, but also several other effects, which suggested influences on dopaminergic mechanisms. To elucidate whether these actions are indirectly mediated by opiate receptors or due to direct influences, we investigated the influence of casomorphin derivatives with high analgesic potency on the yawning behavior of rats, comparing their effects also with those of their des-tyrosine analogues, which exhibit no affinity to opiate receptors.
Yawning behavior can be induced by dopamine receptor agonists, cholinergic agonists, as well as peptide hormones.
Since yawning is elicited only by small doss of the dopamine agonists, it has been proposed that this response may be mediated via dopamine autoreceptors. The stimulation of dopamine autoreceptors and the resulting attenuation of dôpamine release disinhibits a cholinergic link, thus inducing yawning.
This supposed dopaminergic control of yawning offers a useful method to investigate the influence of casomorphins on dopaminergic mechanisms and was used in the present study.
After the first description of APO-induced yawning by Mogiinicka and Klimek (19), the influence of several neuroactive drugs on this dopaminergic mechanism was investigated.
Not only mixed dopamine D1/D2 receptor agonists like apomorphine and peribedil (15,19,28,3 1) and highly selective dopamine D2 receptor agonists (4,13-15,34) but also muscarinic receptor agonists (27,29,32,34) elicited yawning in rats.
The yawning behavior induced by dopamine receptor agonists is blocked by both dopamine D2 receptor antagonists and muscarinic receptor antagonists (4,9,14,19,29,30,33,34). However, yawning is not inhibited by the peripheral anticholinergic agent methylscopolamine or by mecamylamine, a nicotinergic receptor blocking agent. In contrast, the yawning induced by D2 receptor agonists is not blocked by dopamine D1 receptor antagonists (14,32,34).
Therefore, it is hypothesized that yawning involves dopamine D2 receptor stimulation and central muscarinic receptor activation (4,15,32,34). On the other hand, yawning was also prevented by the selective dopamine D1 receptor antagonist SCH 23390. This finding suggested that yawning may not be mediated by autoreceptors, but by a sensitive population of postsynaptically located dopamine receptors (13,20,24-26).
All these results obtained indicate a close interaction between cliolinergic and dopaminergic transmitter systems in yawning and a modulating influence of adrenergic and also serotonergic mechanisms. Therefore, it has to be taken into account that the pharmacological influence of drug-induced yawning is due to different mechanisms of action and cannot exclusively be attributed to dopaminergic mechanisms. Hence, a hypothetical model of a central control mechanism includes a dopaminergic inhibitory-cholinergic exitatory link (9,29,31,32).
Our results show a dose-dependent inhibition of the APOinduced yawning by casomorphin derivatives with opioid activity. These dose-response curves suggest an effect of casomorphin derivatives on dopamine-mediated processes. The APO-induced yawning could be inhibited by the peptides at presynaptic dopamine receptors antagonizing the inhibition of dopamine release by small APO doses. On the basis of their biochemical investigations, Kammerer et ai. postulated an indirect dopaminergic action of [D-Pro4]CM as well (10). They demonstrated an inhibition of dopamine reuptake and an enhanced K'-stimulated release of dopamine by [D-Pro4]CM. A blockade of dopamine receptors was only found using much higher doses than with haloperidol (11). Such a presynaptic dopaminergic disinhibition may possibly al'o decrease the tone of the cholinergic
system activated by physostigmine, thus leading to an inhibition of the physostigmine-induced yawning. Another mode of action of the casomorphin derivatives could be due to the interactions with opiate receptors. Like the tyrosine-containing casomorphin derivatives, morphine inhibited the apomorphine-induced yawning completely. However, only the morphine effect was suppressed by naloxone (8). Therefore, a corresponding action of [D-Pro4]CM on the opiate receptor seems to be most unlikely.
The dopaminergic transmission can be modulated by casomorphin derivatives, thus resulting in a decrease in yawning. The decrease in PHYSO-induced yawning by 5 nmol [DPro4]CM and 10 nmol [D-Phe3JCM may originate from a possible cholinolytic action, too.
The effect of des-tyrosine casomorphins differs in some respect from that of the tyrosine-containing casomorphins. They show a U-shaped dose-response curve as well as an altogether lower effect. [des-Tyr-D-Phe3]CM and [des-Tyr-D-Pip4JCM were not found to influence the PHYSO-induced yawning. However, [desTyr-D-Pro4]CM increased the physostigmine-induced yawning significantly. Nickolson and Berendsen (21) found differences in the effect between the neuroleptic-like [des-Tyr--yjendorphin and haloperidol (5). Whereas haloperidol completely blocked the APO-induced yawning, [des-Tyr-y]endorphin inhibited yawning only partially. The dose-dependent inhibition of yawning showed a similar U-shaped curve like the inhibition by our investigated des-Tyr casomorphins. Contrary to haloperidol, which inhibited yawning in each case, the small yawning rate
obtained with very low APO doses was potentiated by [des-Tyr-y]endorphin. Nickolson and Berendsen concluded that low doses of [des-Tyr-yJendorphin sensitize presynaptic receptors whereas high doses sensitize postsynaptic sites of action (21).
Possibly the serotonergic modulation may play an important role in the yawning behavior. Yawning induced by dopaminergic drugs can be potentiated by decreasing activity of serotonergic neurons, whereas the physostigmine-induced yawning was attenuated. Serotonergic activation had the contrary effect (6,15).
For instance, Holmgren and Urba-Holmgren have found that apomorphine yawning is inhibited but physostigmine yawning is enhanced or not influenced by the 5-HT-uptake blocker citalopram (9). There was a comparable influence of [des-Tyr-DPro4]CM supported by biochemical results in which an inhibition of serotonin reuptake into striatal synaptosomes could be demonstrated (Schräder, personal communication).
Summarizing our own results in the light of these data and interpretations, it is assumed that casomorphin derivatives containing 1 tyrosine modulate dopaminergic transmission. However, it cannot be completely excluded that this effect involves a cholinolytic action resulting in an inhibition of yawning. At least for [D-Pro4JCM, an opioid-like action can be excluded, too. Furthermore, an opiate-like effect can be ruled out with regard to des-tyrosine derivatives by reason of the missing Nterminal tyrosine. Consequently, a modulation of dopaminergic transmission can be assumed without excluding a serotonergic activation by [des-Tyr-D-Pro4]CM.