Opioids, Reward and Addiction: An Encounter of Biology ...

To investigate the regulation of E by opioids, Gudehithlu
et al. (1991) undertook a study where they determined
the levels of E-IR in discrete brain regions,
pituitary, and plasma in various states of chronic morphine
treatment (six morphine pellets in 7 days). They
found that in morphine tolerant/physically dependent
rats, E-IR was significantly decreased in the plasma,
pituitary, and in restricted brain regions (i.e., the hypothalamus
and midbrain). E-IR levels remained unaltered
in the cortex, striatum, hippocampus, amygdala,
hindbrain, and spinal cord. During protracted withdrawal
from morphine, E-IR levels were decreased in
the pituitary, spinal cord, and amygdala, whereas naloxone-precipitated
withdrawal caused E-IR decreases
in the pituitary and hippocampus. Moreover, increases
in E-IR levels were observed in the cortex, midbrain,
and hippocampus. The authors concluded that the endorphin
system is differentially affected in morphine
tolerant/physically dependent and abstinent rats, and
that these changes were brain region-specific.
An interesting finding in the potential regulation of
E by opioids is that of Sweep et al. (1988, 1989). They
demonstrated that i.v. heroin self-administration for
five daily 6-h sessions resulted in a decrease in E-IR
levels in the septum when measured immediately after
the fifth self-administration session. At the time of a
scheduled next session on day 6, 18 h later, the heroin
self-administering animals showed marked decreases in
E-IR in several areas of the anterior limbic system such
as the NAC, septum, hippocampus, and rostral striatum.
No effects were found in the hypothalamus, thalamus,
amygdala, caudal striatum, mesencephalon, or medulla.
Interestingly, similar findings were found in
animals self-administering cocaine. The authors suggested
that the change in levels of -endorphin and
related peptides in these areas might reflect an involvement
of endogenous opioids in processes underlying psychic
dependence. Moreover, these findings are of particular
interest because they address the functional
interface between changes in endogenous opioid levels
and drug dependence, in contrast to studies wherein
drugs are administered by the experimenter.
Several reports have appeared on the opioid regulation
of the brain enkephalin system. Although decreases
(Przewlocki et al., 1979; Gudehithlu et al., 1991) and
increases (Shani and Azov, 1979; Weisman and Zamir,
1987; Tejwani and Rattan, 1997) in enkephalin immunoreactivity
in selected brain regions were reported, a
majority of studies reported a lack of an effect of opioid
treatment on enkephalin immunoreactivity levels in the
brain (Childers et al., 1977; Fratta et al., 1977; Wesche
et al., 1977; Bianchi et al., 1988; Bronstein et al., 1988;
Uhl et al., 1988; Mochetti et al., 1989). Moreover, measuring
the enkephalin synthesis in selected brain regions
(e.g., hypothalamus and striatum), a lack of effect
of several schedules of opioid treatment on enkephalin
OPIOIDS, REWARD AND ADDICTION 361
mRNA was found (Lightman and Young, 1987; Mochetti
et al., 1989; Tjon et al., 1997).
There is increasing evidence that chronic administration
of opioids causes significant changes in the dynorphin
system in selected brain regions. In short, different
schedules of chronic opioid administration (pellets, repeated
s.c. injection, chronic i.c.v. infusion) all caused an
increase in dynorphin peptides (i.e., dynorphin A, dynorphin
B, and -neo-endorphin) in the brain, predominantly
in the dorsal striatum (Weissman and Zamir,
1987; Trujillo and Akil, 1990; Romualdi et al., 1991;
Trujillo et al., 1993). At the same time, the expression of
dynorphin mRNA was decreased in, among others, the
striatum (Romualdi et al., 1989, 1991; Tjon et al., 1997).
In a study by Yukhananov et al. (1993) morphine was
chronically administered through s.c. implanted osmotic
pumps for 5 days. The results showed that the level of
dynorphin A (1–17) remained unaltered in several limbic
brain regions, including the medial frontal cortex,
olfactory tubercle, NAC, and striatum immediately before
(morphine-tolerant/physically dependent state) and
20 h after (protracted withdrawal) the pump was removed.
During long-term discontinuation from morphine,
i.e., after the disappearance of the signs of withdrawal,
the level of dynorphin A was, however,
significantly lowered in the NAC. Tjon et al. (1997) compared
the effects of two different morphine pretreatment
regimens on striatal preprodynorphin gene expression.
It was observed that an escalating dose regimen (10–50
mg/kg, three daily injections for 5 days), which induced
severe physical dependence, caused a transient suppression
of dynorphin mRNA expression in caudate putamen
and NAC, present 1 day, but not 21 days after cessation
of treatment. In contrast, upon repeated intermittent
morphine treatment (10 mg/kg, 14 daily injections), a
decrease in dynorphin mRNA expression in caudate putamen
and NAC was found 1 day, whereas an increase in
both regions was observed 21 days post-treatment. From
these results it might be suggested that dynorphin particularly
participates in mechanisms occurring long after
discontinuation of opioid use.
Thus, there seems to be consensus that the endorphin
and dynorphin system in different brain areas are affected
by opioids. Although the relevance of most of the
observed changes for opioid reinforcement is unclear,
these endogenous opioids, located in limbic areas, might
be involved in psychic dependence and in brain changes
occurring long after discontinuation of drug use.
IV. Intracranial Electrical Self-Stimulation
A. Effects of Opioids
The first report about the effect of morphine on ICSS
was from Olds and Travis (1960). The self-stimulation
behavior was studied over a range of stimulus intensities
in animals with electrodes implanted in the lateral
hypothalamus (LH), septal area, or VTA. Although it