haut de page















haut de page


mise à jour du
27 mars 2003
Opiate-androgen interactions in drug-induced yawning and penile erections in the rats
Hemmie HG Berendsen, Alma J Gower
CNS Pharmacology deprtment Organon International BV, Oss, The Nederlands


Yawning is a readily quantified behavioural response which can be elicited in laboratory animals by various pharmacological agents including dopamine agonists, cholinomimetics and centrally injected ACTH peptides. Drug-induced yawning has been reported for a range of laboratory animals including mouse, rat, guinea pig, cat, dog and monkey.

There is evidence suggesting that irrespective of the agent eliciting the response, drug-induced yawning is subject to androgenic influences. The incidence of yawning produced by either apomorphine or physostigmine is lower in female than in male rats. Castration of male rats reduces the levels of yawning to that typically obtained in females. Furthermore enhancing the androgen levels by pretreatment with dihydro-testosterone (I)HT) permits a level of drug-induced yawning in both female rats and in male castrates which is equivalent to that obtained in normal male animals. Similarly, testosterone treatment increases ACTH-induced yawning in guinea pigs.

Concomitant with yawning, dopamine agonists and ACTH increase the incidence of penile erections in normal rats. Physostigmine does not have this effect. Spontaneous penile erections are markedly reduced or absent in chronically castrated rats but can be restored by testosterone or DHT, indicating that, like yawning, penile erections are androgen-de pendent.

There are several lines of evidence for an interaction between androgens and opiates. Opiate binding sites in rat brain are doubled in chronically castrated animals; this effect can be prevented by repeated injection of testosterone. Intracerebroventricular injection of androsterone produces behavioural effects similar to those produced by opiates including wet dog shakes, analgesia, Straub tail and excess grooming; these effects can be antagonised by naloxone. Also data reported by Cicero implicate an interaction between opiates and androgens on the hypothalamic-pituitary axis controlling LH release; naloxone antagonised but morphine mimicked the effects of testosterone in castrated rats.

In view of this interaction between opiates and androgens and the influence of androgens on yawning and penile erections, we tested whether an opiate-testosterone link was involved in drug-induced yawning and pende erections by investigating the effects of selected drugs on yawning and pende erections induced in intact and in castrated rats. [...]


In accordance with previous studies both apomorphine and physostigmine caused yawning in intact rats but only apomorphine concomitantly caused penile erections. In one experimental situation, however, in which the animal is placed on his back and restrained, the putative dopamine stimulant RDS-127 reduces penile reflexes. Results obtained with restrained rats cannot be compared easily to results obtained with freely moving and unstressed animals, but an increase in ejaculations is also observed under these restrained circumstances.

Yawning induced by apomorphine was markedly reduced in chronically castrated rats but was restored by pretreatment with DHTP, confirming earlier results. Penile erections were abolished by castration and could not be elicited by apomorphine with or without pretreatment with DHTP. Although the absence of penile erections in castrated rats is well documented, the failure to reinstate penile erections with DHTP is at variance with published findings. Under similar conditions of long-term castration, penile erections were restored within 3 days of implanting a 30-mm silastic capsule filled with DHTP. Although the actual dose was not reported, such treatment would undoubtedly result in higher, sustained plasma testosterone levels than those resulting from 125 µg/rat once daily for 3 days as used in the present experiments.

Naloxone partially blocked drug-induced yawning in intact rats. This effect appears to be androgen-dependent since in castrated rats naloxone blocked the increases in yawning occurring in the presence of DHTP but had no effect on the residual apomorphine response in castrated controls which did not receive DHTP. However, there was no evidence of an opposite enhancing action by morphine despite various additional manipulations of the dosing schedule in intact and castrated rats, e.g. repeated daily injections ranging front 1 to 10 mg/kg or implanting 75 mg morphine pellets subcutaneously (data not shown). In fact, morphine reduced drug-induced yawning, an effect which is probably due to sedative side effects.

The effect of DHTP on apomorphine-induced yawning has been accounted for in terms of a permissive action by androgens. The naloxone results suggest that this permissive role is subject to opiate influences. However, both the failure of morphine to modify the effect of naloxone on yawning and penile erections in intact rats and the lack of effect of morphine on the DHTP-induced increases in apomorphine yawning in castrated rats are inconsistent with this hypothesis. From these results it must be concluded that the naloxone-androgen interaction is not mediated via an opiate receptor or, if it is, then it is a subtype of opiate receptor for which morphine is not sufficiently selective.

The inability of DHTP to sustain apomorphine-induced penile erections in castrated rats precludes any comment as to whether opiates modulate the effects of androgens on this response. In normal rats morphine, like haloperidol, blocked apomorphine-induced penile erections whereas naloxone enhanced the response. This latter observation substantiates similar findings of enhancement by naloxone of penile erections induced by norpropylnorapomorphine and apocodeine. Since there is no evidence to suggest otherwise, it is possible that the enhancement of apomorphine-induced penile erections in normal rats by naloxone and the antagonism by morphine is due to direct interaction between dopamine and opiate receptors as obtained with several other dopamine-mediated behaviours.

The effects of haloperidol and atropine in intact rats are in agreement with previous findings that neuroleptics and anticholinergics can block drug-induced yawning in normal animals and accords with a proposed dopaminergic-cholinergic mediation of yawning. The ability of both drugs to block apomorphine-induced yawning in castrated rats, with or without DHTP pretreatment, indicates that their effects are independent of androgen influences. The blockade by both drugs of apomorphine-induced penile erections shows that this effect is also sensitive to both dopaminergic and cholinergic influences. However, the cholinergic influence is likely to be indirect since physostigmine fails to elicit penile erections in the rat but it does cause yawning. Although atropine blocked physostigmine yawning at all doses tested, haloperidol at the lowest dose had an enhancing effect; higher doses caused slight inhibition. The enhancing effect may be explicable in terms of postsynaptic blockade of dopamine receptors by haloperidol thereby preventing inhibition by dopamine on the cholinergic neurones. Yamada and Furukawa reported similar enhancement by fluphenazine of physostigmine-induced yawning.

The relative lack of effects by domperidone, methyl naloxone or methyl atropine on drug-induced yawning or penile erections provides evidence that the induction and the blockade of both responses is centrally, not peripherally mediated. The dose, 10 mg/kg, of methyl atropine which partially antagonised yawning and penile erections is one which blocks central cholinergic receptors.

In the present study we have investigated a possible opiate-androgen interaction in drug-induced yawning and penile erection. However, although a naloxone-androgen interaction in yawning was clearly shown, the results obtained with morphine indicate that this interaction is probably not opiate receptor-mediated.

Finally, while penile erection is clearly androgen-dependent, our experiments do not allow any conslusion on a possible opiate-androgen link.

-Berendsen HG Androgenic influences on apomorphine-induced yawning in rats Behavioral and neural biology 1981; 33; 123-128
-Berendsen HG, Gower AJ Opiate influences on drug-induced yawning in the rat Behav Neural Biol. 1981; 33; 1; 123-128
-Berendsen HG ; AJ Gower Opiate-androgen interactions in drug-induced yawning and penile erections in the rats Neuroendocrinology 1986; 42; 185-1901
-Berendsen H et al Involvement of 5-HT1c-receptors in drug-induced penile erections in rats Psychopharmacology 1990; 101; 57-61
-Gower AJ Effects of acetylcholine agonists and antagonists on yawning and analgesia in the rat Europ J Pharmacology 1987; 139; 79-89
-Gower AJ, Berendsen HH, Broekkamp CL Antagonism of drug-induced yawning and penile erections in rats Eur J Pharmacol 1986; 122; 2; 239-244
-Gower J, Berendsen H et al. Yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity Eur J Pharmcol 1984; 103; 81-89
-Gower AJ Cholinergic mediated yawning and analgesia in rats: differential effects of muscarinic agonists and antagonists. 1987

« It is ironic that testosterone "the male sex hormone," is more closely associated with the yawning rate than with the mounting or intromitting rates » Charles Phoenix
Sexual steroids exert several effects on both central dopaminergic and oxytocinergic systems by acting either at the genomic or membrane level  
credit photo : "Asif A. Ghazanfar and Aristides Arrenberg"
Max Planck Institute for Biological Cybernetics
Tuebingen; Germany.

merci à eux