Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al  
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mise à jour du 28 août 2003
Naunyn-Schmiedeberg's arch Pharmacol
1997; 355; 595-600
Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: involvement of nitric oxide
MR Melis, S Succu, U Iannucci,A Argiolas
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Introduction : Penile erection and yawing are two different behavioral patterns that often occur concomitantly in different experimental conditions. While the importance of penile erection in reproduction does not need to be stressed, it is pertinent to recall that yawning, alone or associated with stretching, is considered an ancestral vestige surviving through evolution that subserves the purpose of arousal. Dopaamie receptor agonists (i.e. apomorphine) and oxytocine are among the most studied substances that induce both penile erection and yawing. Both compounds induce these beliavioral responses by acting in the paraventricular nucleus of the hypothalamus (PVN) apparently hy activating central oxytocinergic transmission. Accordingly, these dopamine and oxytocin-induced responses are prevented by electrolytic lesions of the PVN, which deplete central oxytocin, and by oxytocin receptoi- antagonists given into the ateral ventricles
Recently, we found that the induction of penile erection and yawning by dopamine receptor agonists and oxytocin depends on a normal activity of nitric oxide synthase in the PVN, because the inhibition of this enzyme in this nucleus, but not in other brain areas prevents these behavioral responses induced either by apomorphine or oxytocin. Interestingly, the PVN is one of the richest brain areas containing NO synthase, which among others has been identified also in the cell bodies of oxytocinergic neurons.

The involvement of NO in the induction of penile erection and by dopamine receptor agonists and hy oxytocin has been recently substantiated by showing, that either apomorphine or oxytocin-induced penile erection and yawning, are associated to an increase of the concentration of NO2 and NO3, the reaction products of newly synthetized NO with O2 which are an indirect but reliable indicator of NO production by biological tissues in vivo, in the dialysate collected from a vertical microdialysis probe implanted in the PVN. Since apomorphine- and oxytocin-induced penile erection and yawning are prevented also by the opiate morphine given systemically or directly into the PVN, we studied whether this effect of the opiate on penile erection and yawning induced by apomorphine and oxytocin was related to changes of the NO production in the PVN of male rats by in vivo microdialysis. [...]

Discussion: The present results show that morphine given either systemically or i.c.v. or into the PVN prevents the the increase of concentration of NO2 and NO3, induced hy the dopamine receptor agonist apomorphine or by oxytocin, in the paraventricillar dialysate obtained frome male rats implanted with a vertical microdialysis probe. In agreement with previous finding's showing that both morphine and oxytocin, at the doses used in this study activates NO synthase in the PVN to induce these behavioral responses, the prevention by morphine of the NO2 and NO3 increase is correlated to the well known prevention by the opiate injected in the PVN of penile erection and yawning induced by the above compounds (Melis et al. 1992b). The effect of morphine is niediated by the stimulation of opioid receptors, being prevented by the prior administration of the opioid receptor antagonist naloxone?
Since U-69,593, an opioid receptor agonist that is 500 times more selective than morphine on the kappa opioid receptor subtype, is ineffective in preventing apomorphine and oxytocin responses either when injected i.c.v. or into the PVN, these findings suggest that morphine prevents the activation of NO synthase, penile erection and yawning induced by apomorphine or oxytocin by acting on opioid receptors of the µtype located in the PVN. It is likely that these receptors are located in the cell bodies of parvocellular oxytocinergic neurons projecting to extrahypothalarnic brain areas and mediating these behavioral responses. Accordingly, inhibitory µ opioid receptors are present in the cell bodies of paraventricular oxytocinergic neurons .

In line with the hypothesis discussed above. morphine might then prevent NO production in the PVN by acting on opioid receptors, whose activation interfere with the rnechanisms responsible for the activation of NO synthase by apomorphine and oxytocin. In this regard, it is pertinent to recall that

  1. the prevention by morphine of the NO2 and NO3 increase in the PVN dialysate would reflect almost exclusively a decreased conversion of L-arginine to NO that is in turn oxidized mainly to NO2 and to a lesser extent to NO3, as found in other biological fluids not containing blood cells
  2. the PVN is one of the richest brain areas in NO synthase
  3. the enzyme has been localized in the cell bodies of oxytocinergic neurons. Since the blockade of N-type voltage dependent calcim channels by nannogram amounts of omega-conotoxin injected in the PVN prevents penile erection and yawning induced either by oxytocin or by apomorphine, it is temting to speculate that opioid receptors are negatively coupled to CA++ channels and that their stimulation by morphine leads to a decline in Ca++ influx which in turn causes a decresa in the activity of NO synthase, a calcium-calmodulin dependent enzyme in the cell bodies of oxytocinergic neurons medianting penile erection and yawning. The decreased NO formation would in turn reduce the oxytocinergic transmission by a yet unknown mechanisin, apparently unrelated to the activation of guanylate cyclase, decreasing thereby the behavioral responses.

    However, the present results do not rule out other mechanisms by means of which morphine might interfere with NO synthase activation induced by apomorphine or oxytocin. For instance morphine might inhibit directly NO synthase or alter indirectly its activity in oxytocinergic neurons by modulating the release of other neurotransmittters / neuromudulators in the PVN. However, the first possibility is unlikely, because

  4. morphine alone does not cause any decrease in basal N02 and NO3 levels
  5. acute or chronic morphine does not alter NO synthase activity in brain homogenates nor its expression. as measured by the amount of NO-synthase mRNA in several mouse brain areas.

    Interactions between opioids and NO have been shown to occur in other central functions. For instance NO seems to be involved in the expression of opioid antinociception, tolerance and dependence, although with some discrepancy. In these studies either facilitatory or inhibitory effects of NO on morphine effects were found. The present results show that morphine and NO interact in opposite manner in the control of penile erection and yawning at paraventricular level. In particular the findings suggest that µ opioid receptor stimulation in the PVN decreases NO synthase activity to inhibit these behavioral responses induced by dopamine receptor agonists or by oxytocin.