Editorial: Opioids and opioid-use disorders

Molecular Brain Research, 1998

The induction of c-fos mRNA in rat brain due to morphine treatment was analyzed by in situ hybridization. A single dose of up to 100 mgrkg given to naive rats elicited only a weak c-fos expression. However, rats that were repeatedly pretreated with morphine displayed a marked c-fos induction in a few brain areas in response to morphine application. These brain areas essentially comprised the dorsal striatum, the shell of the nucleus accumbens, and some cortical areas. The c-fos signal was transient and not due to a residual withdrawal. Naloxone-precipitated withdrawal led to a more intense c-fos expression which also encompassed a greater range of brain areas. A similar but weaker pattern was observed in case of spontaneous withdrawal. A low morphine dose suppressed the c-fos expression nearly completely and was not sufficient to elicit the morphine-like expression pattern of c-fos. The brain areas which responded strongly to withdrawal included the piriform cortex, septal and hypothalamic nuclei and parts of the thalamus. Taken together, our data indicate that in certain circumscribed brain areas including the dorsal striatum and the shell of the nucleus accumbens, a sensitization towards morphine takes place at the molecular level. These areas responded to morphine with an elevated c-fos expression only when morphine was repeatedly given previously. Sensitization processes are thought to be important for opiate dependence, in particular for the increased craving for the drug. Furthermore, our data indicate that in case of repeated application signs of withdrawal appear after each morphine dose at the molecular level. Repeated events of withdrawal were also implicated in the establishment of a drug dependence state. q 1998 Elsevier Science B.V. All rights reserved.

Experimental Neurology, 1979

…, 2009

A history of intermittent exposures to drugs of abuse can cause long-term changes in acute behavioural responses to a subsequent drug exposure. In drug-naive rats, morphine can elicit intermittent cataleptic postures followed by sustained increases in locomotor activity. Chronic intermittent morphine treatment can reduce catalepsy and increase locomotor behaviour and stereotypy induced by morphine, even after prolonged periods of abstinence. The nucleus accumbens and limbic basal ganglia circuitry are implicated in the expression of various morphine-induced motor behaviours and catalepsy. We examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the basal ganglia following a subsequent morphine challenge administered after a period of drug abstinence. We found that such exposures increased c-Fos induced by a morphine challenge in accumbens core regions that were immunoreactive for the m-opioid receptor, and this correlated with the frequency of stereotypic behaviours displayed by the rats. We also found that a history of morphine exposures increased c-Fos in the ventrolateral striatum in response to a morphine challenge following 14 d but not 24 h of drug abstinence. In contrast, such a history induced acute Fras in the nucleus accumbens in response to a morphine challenge following 24 h but not 14 d of morphine abstinence. These data provide further confirmation that psychomotor sensitisation induced by repetitive morphine exposure involves longterm neuroadaptations in basal ganglia circuitry particularly at the level of the nucleus accumbens.

Brain Research, 2013

The nucleus accumbens (NAc) and prefrontal cortex (PFC) are two parts of neuronal reward circuit involved in motivated and goal-directed behaviors. Some data suggest that morphine is toxic to neurons and induces apoptosis, while other evidence shows that morphine could have beneficial effects against cell death. This study was designed to evaluate the effect of morphine on apoptosis by measuring the expression of apoptotic proteins in two important regions, the NAc and PFC, in the rat brain's reward circuitry. Morphine subchronic administration in different doses (0.5, 5 and 10 mg/kg) in conditioned place preference (CPP) paradigm (3 times in 3 days, for each dose in each group of rats) was used to induce its rewarding effect. Then, the expression of four apoptotic factors; Bax, Bcl2, caspase3 and PARP, in the NAc and PFC were assessed using the Western blot technique. All of morphine-treated groups showed increase of apoptotic factors in these regions. In the NAc, morphine significantly increased the Bax/Bcl-2 ratio, caspase3 and PARP in the lowest dose (0.5 mg/kg) but in the PFC considerable increase was seen in dose of 5 mg/kg. Elevation of apoptotic factors in the NAc and PFC implies that morphine can affect the molecular mechanisms which interfere with apoptosis through different receptors. Our findings suggest that the NAc and PFC may have a different distribution of receptors which become active in different doses of morphine.

Brain Research, 1992

In the present experiments, we examined the roles of opiate receptor subtypes in the nucleus accumbens in spontaneous motor behavior and responding for conditioned reward. Locomotor activity was measured using photocell cages and reward-related responding was determined in the conditioned reinforcement (CR) paradigm. In the CR paradigm, food-deprived rats were trained to associate a compound stimulus with food reward, and were subsequently tested for responding on a lever that resulted in presentation of the compound stimulus alone, in all experiments, various opiate agonists were microinjected into the nucleus accumbens. In the activity studies, morphine sulfate (mixed p, and 6 agonist; 0.025, 0.25 and 2.5 #g/0.5/.tl) caused an initial inhibition followed by a disinhibition of activity while [t~-Ala2-MetS]-enkephalin (DALA) (mixed p, and 6 agonist: 0.25, 2.5 and 5.0 p,g/0.5 p,I) elicited an immediate potentiation of locomotor activity. The behavioral profile following [D-Ala2-N-Me-Phe4-Gly-ol'~]-enkephalin (DAMGO;/.t agonist; 0.01, 0.1 and 1.0/xg/0.5 p,I) was similar to morphine, in contrast, [o-Pen:'5]-enkephalin (DPEN; agonist; 0.02, 0.2 and 2.0 p,g/0.5 p,I) induced an immediate, but relatively short-lasting activation. Both DALA and DPEN also dose-dependently enhanced rearing; rearing was not affected by the other treatments. U50,488H (r agonist; 0.0186, 0.186 and 1.86 p,g/0.5 #1) had no effect on any aspect of motor activity. In contrast to effects on motor activity, none of the opiate agonists significantly potentiated responding for CR, although morphine infusion did tend to increase responding somewhat, in contrast, D-amphetamine (20 ~g/0.5 #l) did potentiate responding, as previously reported. A distinction between the effects of opiates and psychostimulants on reinforced responding is hypothesized based on differential modulation of dopamine release, These experiments demonstrate a dissociation of the effects of opiates on locomotor activity and reward-related responding.

Basic and clinical neuroscience, 2013

This study has examined the functional importance of nucleus accumbens (NAc)-ventral tegmental area (VTA) interactions. As it is known, this interaction is important in associative reward processes. Under urethane anesthesia, extracellular single unit recordings of the shell sub-region of the nucleus accumbens (NAcSh) neurons were employed to determine the functional contributions of the VTA to neuronal activity across NAcSh in rats. The baseline firing rate of NAcSh neurons varied between 0.42 and 11.44 spikes/sec and the average frequency of spontaneous activity over 45-minute period was 3.21±0.6 spikes/sec. The majority of NAcSh neurons responded excitatory in the first and second 15-min time blocks subsequent to the inactivation of VTA. In the next set of experiments, eight experimental rats received morphine (5 mg/kg; sc). Three patterns of neuronal activity were found. Among the recorded neurons only three had an increase followed by morphine administration. Whereas the other three neurons were attenuated following morphine administration; and there were no changes in the firing rates of the two neurons left. Finally, unilateral reversible inactivation of VTA attenuated the firing activity of the majority of ipsilateral NAcSh neuron in response to morphine, except for a single cell. These results suggest that transient inactivation of VTA reduces the ability of neurons in the NAcsh to respond to systemic morphine, and that NAcSh neuron activity depends on basal firing rate of VTA inputs.

Pharmacology Biochemistry and Behavior, 1996

Morphine and naloxone, IP or locally, affect extracellular acetylcholine in the accumbens and prefrontal cortex. PHARMACOL BIOCHEM BEHAV 53(4) 809-816, 1996.-In rats with microdialysis probes in the nucleus accumbens (NAc) or prefrontal cortex (PFC), intraperitoneally (IP) delivered morphine on the 8th day of escalating doses decreased extracellular ACh in the NAc. On day 9, naloxone (5 mg/kg) precipitated withdrawal and increased the release of ACh. When morphine and methylnaloxonium were given locally into the NAc by reverse dialysis, the opiate again decreased extracellular ACh, and the opiate antagonist increased it. These effects were proportional to the dose of local infusions. Local morphine had the same ACh-lowering effect in morphinedependent and nondependent rats, whereas local methylnaloxonium increased extracellular ACh significantly more in morphine-dependent animals. Systemic and local effects on ACh systems in the PFC were more complicated and showed some relation to locomotor activity. The results suggest that intrinsic ACh neurons in the NAc have a special relationship to opiate reinforcement such that extracellular ACh is low in response to morphine and high during withdrawal. Thus, low ACh may correlate with opiate reward, and high ACh with aversion. Microdialysis Acetylcholine Morphine Opiates Methylnaloxonium Addiction Withdrawal Nucleus accumbens Prefrontal cortex Rats

Behavioural Brain Research, 2007

Mice self-administer morphine into the lateral septum (LS), but the neuronal connections underlying this behaviour remain unknown. The present study tested whether the acquisition of intra-LS morphine self-administration depends on dopaminergic mechanisms. Mice were allowed to self-inject morphine (5 or 20 ng/50 nl) or vehicle directly into the LS using a spatial discrimination Y-maze task. Fos imaging was used to evaluate neuronal activation in cerebral structures directly connected to the LS or belonging to the dopaminergic system. The involvement of dopaminergic and opioidergic mechanisms was assessed by pre-treating naive mice peripherally with the D1 antagonist SCH23390, the D2/D3 antagonist sulpiride or the opiate antagonist naloxone before daily self-administration sessions. Mice acquired self-administration behaviour for intra-LS morphine that was associated with increased Fos expression in the ventral tegmental area (VTA), dorsal and ventral striatum and prefrontal cortex. Pre-treating animals with naloxone, SCH23390 or sulpiride completely prevented them from acquiring intra-LS morphine self-administration. All three antagonists consistently blocked Fos expression in the prefrontal cortex, but not in the VTA and striatum. Taken together, our results show that morphine self-administration into the LS depends on dopaminergic (D1 and D2/D3) and opioidergic mechanisms. Furthermore, they suggest that opioid peptides released in the LS could participate in regulating the activity of mesotegmental dopaminergic neurons.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1998

Experimental Neurology, 1972