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
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
the PVN is one of the richest brain areas in
NO synthase
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
morphine alone does not cause any decrease
in basal N02 and NO3 levels
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.
