Agmatine inhibits morphine-induced locomotion sensitization and morphine-induced changes in striatal dopamine and metabolites in rats

The effects of agmatine on morphine-induced locomotion sensitization and morphine-induced changes in extracellular striatal dopamine (DA) and DA metabolites were studied. The locomotor response to morphine challenge (3 mg/kg, s.c.) was enhanced in rats 3 days after repeated morphine administration, indicating development of locomotion sensitization. In vivo microdialysis demonstrated a significant increase in striatal basal levels of the DA metabolites DOPAC and HVA, but not in DA itself, and an increase in DA response to morphine challenge in rats 3 days after withdrawal. Agmatine (1, 10, 80 mg/kg) inhibited morphine-induced locomotion sensitization and the changes in DA noted above. Idazoxan attenuated the effects of agmatine on locomotion, suggesting that the effects are mediated by imidazoline receptors. In addition, repeated morphine also increased the expression of tyrosine hydroxylase mRNA in the VTA after 4 days of morphine pretreatment, while decreasing the expression of dynorphin mRNA at 3 days after withdrawal. Agmatine inhibited morphine-induced changes in dynorphin, but not in tyrosine hydroxylase mRNA expression. These data suggest that agmatine, likely by activating imidazoline receptors, inhibits morphine-induced locomotion sensitization and morphine-induced changes in extracellular DA and in dynorphin expression. Thus, agmatine deserves further study as an anti-opioid medication.     

Drug dependence, synaptic plasticity, and tissue plasminogen activator

The mesocorticolimbic dopaminergic system plays an important role in the reinforcing effects of drugs of abuse, and the activity-dependent synaptic plasticity of the system is involved in drug dependence. A DNA microarray screening revealed that the expression levels of tissue plasminogen activator (tPA) mRNA in the nucleus accumbens of morphine- or methamphetamine-dependent rats were significantly increased compared with those in control animals. Since tPA plays a role in synaptic plasticity, we hypothesized that tPA may contribute to the development of drug dependence. Single and repeated morphine treatment as well as repeated methamphetamine treatment induced tPA mRNA expression in the nucleus accumbens, which was associated with an increase in the enzyme activity. Conditioned place preference induced by morphine was markedly reduced in mice with a targeted deletion of the tPA gene (tPA-/- mice), being accompanied by a loss of morphine-induced dopamine release. Similarly, methamphetamine-induced conditioned place preference and locomotor sensitization were reduced in tPA-/- mice. The defects of morphine-induced hyperlocomotion as well as methamphetamine-induced locomotor sensitization in tPA-/- mice were reversed by microinjection of exogenous tPA or plasmin into the nucleus accumbens. These results support our hypothesis that tPA plays a role in long-lasting neuronal changes related to drug dependence.     

Inhibitory effects of paeonol on morphine-induced locomotor sensitization and conditioned place preference in mice

The inhibitory effects of paeonol, a major compound of Paeoniae radix, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated through behavioral experiments. A single administration of morphine produces hyperlocomotion. Repeated administration of morphine develops sensitization (reverse tolerance), a progressive enhancement of locomotion, which is used as a model for studying the drug-induced drug-seeking behaviors, and CPP, which is used as a model for studying drug reinforcement. Paeonol inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, paeonol inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of paeonol. These results provide evidence that paeonol exerts anti-dopaminergic activity, and it is suggested that paeonol may be useful for the prevention and therapy of these adverse actions of morphine.     

Morphine-induced sensitization in mice: changes in locomotor activity by prior scheduled exposure to GABAA receptor agents

This study investigated the effects of a gamma-amino-butyric acid type A (GABAA) receptor agonist and antagonist on morphine-induced locomotor sensitization in male albino mice. Subcutaneous administration to mice of a high dose of morphine (30 mg/kg), but not lower doses (5, 10 and 20 mg/kg) increased locomotion. The maximum locomotor activity was achieved during a 20-min measurement period. The locomotor response to a low dose of morphine (5 mg/kg, subcutaneously) given on day 9 was enhanced in mice pretreated with morphine (7.5, 15 and 30 mg/kg/day x 3 days), indicating that sensitization had developed. Three-day intracerebroventricular (i.c.v.) administration of the GABAA receptor agonist, muscimol (0.025, 0.05, 0.1 and 0.2 microg/mouse/day) significantly decreased both morphine-induced motor stimulation and locomotor sensitization. On the other hand, a 3-day pretreatment with the GABAA-receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/mouse/day) reduced morphine (15 mg/kg)-induced locomotor sensitization. Repeated i.c.v. injections of a lower dose of bicuculline (0.25 microg/mouse/day x 3 days) by itself also decreased morphine-induced locomotion. Furthermore, repeated i.c.v. administration of bicuculline (0.25, 0.5 and 1 microg/mouse/day x 3 days) decreased the effect of i.c.v. injection of muscimol (0.1 microg/mouse/day x 3 days) on locomotor activity induced by morphine (5 mg/kg) in both control and sensitized mice. The magnitude of this response was, however, variable. The results indicate that GABAA receptors might be involved in the acquisition of morphine-induced sensitization.     

Inhibitory effects of glycine on morphine-induced hyperactivity,reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 mg/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

The role of mu opioid receptors in psychomotor stimulation and conditioned place preference induced by morphine-6-glucuronide

Previous studies have shown that morphine-6-glucuronide (M6G), a metabolite of morphine, induces reward and psychomotor stimulation but the role of the mu opioid receptor in these actions of the drug is not fully characterized. Thus, using mice lacking exon-2 of the mu opioid receptor and their wild-type littermates/controls, we determined the role of this receptor in psychomotor stimulation, sensitization, and conditioned place preference (CPP) induced by M6G. For comparison, we also assessed the role of the mu opioid receptor in the rewarding action of morphine. For the measurement of locomotor activity and sensitization, mice were habituated to motor activity chambers for 1h, then injected with M6G (10mg/kg) and locomotor activity was recorded for an additional 1h. The same treatment was given for five days and mice were tested for sensitization a week later. For the CPP experiments, mice were tested for baseline place preference on day 1, then received single or repeated alternate-day saline/drug or drug/saline conditioning and tested for CPP the following day. Mice were also tested for CPP under a drugged state. M6G induced psychomotor stimulation, a response that was enhanced upon repeated administration of the drug, showing that locomotor sensitization developed to the motor stimulatory action of M6G. However, M6G induced a weaker CPP response compared to morphine. None of these actions of M6G was detected in mice lacking the mu opioid receptor. Together, the current results suggest that M6G induces psychomotor stimulation and a weaker rewarding action via the mu opioid receptor.     

Morphine-induced behavioral sensitization increased the mRNA expression of NMDA receptor subunits in the rat amygdala

This study was designed to evaluate the effect of repeated morphine treatment on rat behavioral responses. In the genetic section, the mRNA expression of NMDA receptor subunits (NR1 and NR2A) was measured in certain areas of the male rat brain (striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala). In the behavioral section, the effect of repeated morphine treatment on animal models such as locomotion, oral stereotypy, and state-dependent memory in a passive avoidance test was evaluated in the presence or absence of MK801 (NMDA receptor antagonist). Our results showed that chronic morphine treatment, followed by a 7-day (but not 24-hour) washout period, potentiated the effect of test doses of morphine, which is referred to as behavioral sensitization. Meanwhile, pretreatment of animals with MK801 (0.1 and 0.25 mg/kg), 30 min before a test dose of morphine (5 mg/kg), failed to attenuate the locomotion and oral stereotypy in the behavioral sensitization state. Interestingly, a higher dose of MK801 (0.25 mg/kg) decreased memory retrieval induced by morphine (2.5 mg/kg) in state-dependent memory. This effect may be due to the intrinsic motor enhancer property of higher doses of MK801, rather than the blockade of NMDA receptors. It can be concluded that MK801 does not affect morphine-induced behavioral sensitization in the expression phase. In the genetic section of the study, results of quantitative real-time RT-PCR clearly indicated that morphine sensitization increased the expression of NMDA receptor subunits mRNA in the amygdala (NR1 by 104% and NR2A by 85%), while the other areas of the brain were unaffected. Maenwhile, no change in the mRNA levels was observed in non-sensitized animals (chronic morphine treatment followed by a 24-hour washout period). In summary, the present study indicates that repeated morphine treatment followed by long-term (7-day washout) induces behavioral sensitization and causes a delayed increase in mRNA levels of NMDA receptor subunits in the rat amygdala. Meanwhile, it has previously been reported that the amygdala is involved in behavioral sensitization. Thus, it can be concluded that the increase in NMDA receptor expression is associated with morphine-induced behavioral sensitization.     

The effect of acamprosate on the development of morphine-induced behavioral sensitization in rats

Recently we have shown that the alcohol anti-craving drug acamprosate (calcium acetylhomotaurinate), a functional N-methyl-D-aspartate (NMDA) receptor antagonist which is used therapeutically to prevent relapse in weaned alcoholics, was also effective in suppressing (1) conditioned place aversion induced by morphine withdrawal, and (2) expression of morphine-induced behavioral sensitization. Here, we addressed the question of whether the development of behavioral sensitization, induced by daily injections of morphine (10 mg/kg) over a period of 10 days, could also be suppressed by repeated pretreatment with acamprosate (200 mg/kg). Repeated intermittent injections of morphine produced sensitization of locomotor activity and sniffing behavior. Acamprosate did not block the development of morphine-induced behavioral sensitization. This lack of effect on the development of this phenomenon is inconsistent with the view that NMDA receptor antagonists block the development of sensitization. We suggest that this may derive from the relatively low NMDA receptor-specific antagonism of acamprosate as compared to other NMDA receptor antagonists used in this model. In conclusion, the effect of acamprosate on morphine-induced behavioral sensitization seems to be restricted to the expression of this phenomenon.     

Morphine-6-glucuronide-Induced Locomotor Stimulation in Mice: Role of Opioid Receptors

Abstract: Morphine-6β-glucuronide is a major metabolite of morphine with potent analgesic actions. To explore the importance of this opiate when administered as a drug by its own or in morphine action, we studied the locomotor activity response to morphine and morphine-6-glucuronide in drug-naive C57 BL/6JBom mice. The effects of administration of the two opiates on a battery of 7 different locomotor activities were studied and compared to saline controls. A dose of 20 μmol/kg morphine-6-glucuronide resulted in more locomotion than the same dose of morphine, while at higher doses (up to 120 umol/kg), similar increases for most locomotor behaviours were recorded for both drugs. Pretreatment with naltrindole indicated that the S-receptors play an equivalent but minor role in mediating both morphinc-6-glucuronide and morphine hyperlocomotion. Administration of high naltrexone doses (10 mg/kg) completely abolished the locomotor stimulation induced by both opiates. However, at intermediate naltrexone doses of 0.25 and 0.5 mg/kg, morphine-induced behaviours was completely inhibited while morphine-6-glueuronide induced behaviours demonstrated partial resistance to naltrexone inhibition. The μ₁-specifie receptor antagonist naloxonazine caused 75% reduction of morphine induced behaviours and only 50% inhibition of morphine-6-glucuronide induced behaviors. Taken together our observations indicated general similarity but also marked differences between morphine and morphine-6-glucuronide with respect to opiate receptors mediating the locomotor stimulatory effect.     

Dopaminergic mechanisms mediating the long-term expression of locomotor sensitization following pre-exposure to morphine or amphetamine

The role of dopaminergic mechanisms in opiate- and psychostimulant-induced long-term locomotor sensitization was investigated. To that aim, rats were behaviourally sensitized with morphine or amphetamine and 3 weeks after cessation of treatment challenged with various direct and indirect dopamine agonists. Both morphine- and amphetamine-pretreated rats displayed sensitization of the locomotor effects of amphetamine, cocaine, and the selective dopamine reuptake inhibitor GBR-12909. Sensitization of the locomotor stimulant effects of the dopamine D₂/D₃ receptor agonist quinpirole was observed in amphetamine- but not morphine-pretreated rats. In contrast, morphine-, but not amphetamine-pretreated rats appeared hyposensitive to the locomotor inhibitory effects of a low, presumably D₂-autoreceptor selective, dose of quinpirole. Neither pretreatment induced sensitization to the dopamine D₁/D₂ agonist apomorphine or the dopamine D₁ agonist SKF-82958. In fact, the locomotor stimulant effects of SKF-82958 appeared to be decreased in animals pre-exposed to amphetamine. These results suggest that functional changes in presynaptic dopamine release mechanisms represent common neuroadaptations involved in the long-term expression of morphine- and amphetamine-induced locomotor sensitization. Presynaptic dopamine D₂ and postsynaptic D₂ and/or D₃ receptors are differentially involved in the expression of morphine- and amphetamine-induced locomotor sensitization. In a parallel study, we report that all of the drugs that elicited sensitized locomotor responses in morphine- or amphetamine-pretreated rats caused reinstatement of previously extinguished heroin- or cocaine-seeking behaviour, respectively. Taken together, these data suggest a marked relationship between drug-seeking behaviour and drug sensitization. Received: 22 May 1998/Final version: 12 October 1998     

Morphine-induced antinociception in the formalin test: sensitization and interactions with D1 and D2 dopamine receptors and nitric oxide agents

In this study, the effects of dopamine receptor antagonists and nitric oxide agents on morphine-induced sensitization in the formalin test in mice have been investigated. Repeated daily intraperitoneal administration of morphine (30 mg/kg for 3 days) followed by a 11-day wash out period increased morphine-induced antinociception in the formalin test, which may be due to sensitization. The antinociceptive response to higher doses of morphine (6 and 9 mg/kg) but not 3 mg/kg was significantly increased in sensitized animals compared with control groups. Pretreatment of animals with an opioid receptor antagonist, naloxone (4 mg/kg), during repeated administration of morphine, attenuated the morphine-induced sensitization. In the second part of the study, the animals received SCH23390 (D1 receptor antagonist), sulpiride (D2 receptor antagonist), L-Arg (nitric oxide precursor) and NG-nitro-L-Arg methylester (nitric oxide synthase inhibitor) during repeated morphine administration, to evaluate the role of dopamine receptor antagonists and nitric oxide agents in this phenomenon. Pretreatment of animals with NG-nitro-L-Arg methylester (20 mg/kg) and sulpiride (100 mg/kg) during morphine sensitization decreased the antinociceptive response to higher doses of morphine in the formalin test. It is concluded that D2 dopamine receptor and nitric oxide mechanisms may be involved at least partly in morphine-induced sensitization in the formalin test.     

The involvement of noradrenergic transmission in the morphine-induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment.

1. Our previous studies suggest that in addition to the cerebral dopaminergic systems the noradrenergic ones have a crucial role in the morphine-induced behavioural sensitization in mice. Therefore the effects of alpha2-adrenoceptor antagonist, idazoxan (1 and 3 mg kg(-1), i.p.) on morphine-induced locomotor hyperactivity as well as on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in mice withdrawn for 3 days from 5 day repeated morphine treatment. The concentrations of NA, free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) were determined. 2. Acute morphine (10 mg kg(-1), s.c.) increased locomotor activity in control and in morphine-withdrawn mice; idazoxan alone did not alter the activity. Idazoxan pretreatment did not alter the locomotor hyperactivity induced by acute morphine in control mice but potentiated it in morphine-withdrawn mice. 3. Acute morphine elevated MOPEG less but increased DOPAC and HVA more clearly in morphine-withdrawn mice than in controls, and decreased 3-MT only in controls. Idazoxan alone did not alter the NA or DA metabolite concentrations in control mice, but elevated MOPEG as well as DOPAC in morphine-withdrawn mice. 4. In control mice idazoxan enhanced acute morphine's elevating effect on MOPEG. In withdrawn mice idazoxan counteracted the tolerance so that acute morphine elevated MOPEG in these mice to about similar level as in controls. 5. Idazoxan pretreatment abolished the HVA increasing effect of acute morphine both in control and withdrawn mice. In control mice idazoxan enhanced morphine's elevating effect on DOPAC and abolished morphine's decreasing effect on 3-MT. Idazoxan did not alter morphine's effects on DOPAC or 3-MT concentrations in withdrawn mice. 6. Our results show that in morphine-withdrawn mice idazoxan pretreatment reveals the morphine-induced locomotor sensitization. This most probably occurs by overcoming the tolerance towards the acute morphine-induced increase of cerebral NA turnover and release. It is suggested that in mice the cerebral noradrenergic in addition to the dopaminergic systems are major determinants of the behavioural sensitization to morphine.     

Morphine sex-dependently induced place conditioning in adult Wistar rats

The present study was conducted to investigate the potential sex-differences in morphine-induced conditioned place preference. A 3-day unbiased conditioning procedure was used to establish conditioned place preference in adult male and female Wistar rats (weighing 200-250 g). The effect of morphine on locomotor activity of subjects was also studied. Naloxone (0.5-2 mg/kg, i.p.), a selective antagonist of mu-opioid receptor or sulpiride (0.5-2 mg/kg, s.c.), a selective antagonist of dopamine D(2) receptor was administered, during conditioning, to indicate the receptor-mediated mechanisms governing upon possible sex-differences to the opioid response. Results show that morphine (0.5-10 mg/kg, s.c.) differently produced a significant place preference in female and male Wistar rats. Although, the opioid maximum response in both sexes was observed at 7.5 mg/kg, but, it was found that female rats acquired conditioned place preference at a lower dose (0.5 mg/kg, s.c.) of morphine compared to male rats. Moreover, the increase in morphine-induced response at higher doses (5-10 mg/kg, s.c.) was more pronounced in females than the males, indicating that female Wistar rats are more sensitive to the place conditioning induced by morphine. Also, the females were more sensitive to locomotor activation induced by morphine at least at one dose (7.5 mg/kg). Animals' body-weight at 10 mg/kg of opioid was increased, the effect that was not dependent to sex. The results also demonstrate that naloxone (1 and 2 mg/kg, i.p.) induced a significant place preference in two sexes with no significant effect on animals' locomotor activity. The antagonist in males but not in females showed a significant effect on animals' body-weight. Naloxone (0.5-2 mg/kg, i.p.) prior-administration to morphine, during conditioning, attenuated the opioid response in two sexes. The attenuation of the morphine response was more pronounced in males than the other sex at the higher dose (2 mg/kg) of the antagonist. In addition, the preadministration of naloxone, during morphine conditioning, both attenuated the drug-induced hyperactivity in females and decreased the animals' body-weight, albeit more effectively in females than the males. Sulpiride injections (1 and 2 mg/kg s.c.), during the conditioning period, induced a significant aversion in males but not in females with no significant effect either on locomotor activity or body-weight in both sexes. When sulpiride (0.5-2 mg/kg, s.c.), during conditioning, was morphine pre-injected, the antagonist at higher doses significantly attenuated the opioid response in males, reflecting the involvement of dopamine D(2) receptor in sex-dependent morphine-conditioned place preference. Prior-injections of sulpiride to morphine produced a significant effect on locomotor activity of females. The effect of the antagonist preinjections on body-weight was also observed in males. Present results indicate sex-differences both in reinforcing and locomotor activity effects of morphine in Wistar rats.     

The modulatory actions of dopamine D2/3 agonists and antagonists on the locomotor-activating effects of morphine and caffeine in mice

Morphine produces robust increases in locomotor activity in mice. Recent data indicate that dopamine (DA) D2/3 agonists attenuate the discriminative stimulus and antinociceptive effects of mu opioid agonists such as morphine. The present study was designed to determine the extent to which D2/3 receptor activation and blockade can modulate morphine-induced locomotion using a novel cumulative dosing procedure in Swiss-Webster mice. The results indicate that morphine-induced locomotion is nonsignificantly attenuated by the D2/3 agonists quinelorane and quinpirole, whereas the D2/3 antagonists eticlopride and nafadotride, as well as the partial D2/3 agonist BP897, significantly reduced morphine-induced locomotion. To determine the specificity of this modulation, these agonists and antagonists were examined in combination with caffeine, a drug that also indirectly alters DAergic activity. Unlike the effects on morphine, caffeine-induced locomotion was unaltered by eticlopride, nafadotride and BP897, but was attenuated by quinelorane and quinpirole. These results indicate that modulation of D2/3 receptors can, in turn, alter the locomotor-activating effects of morphine.     

Roles of BDNF, dopamine D3 receptors, and their interactions in the expression of morphine-induced context-specific locomotor sensitization

Drug seeking, craving, and relapse can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. Previous studies indicated that the dopamine D₃ receptor (Drd3) might be involved in the expression of drug-conditioned responses in rats, and brain-derived neurotrophic factor (BDNF) could modulate Drd3 expression in the nucleus accumbens (NAc). However, the involvement of neural regions with Drd3 activation and the underlying interaction between BDNF and Drd3 in the expression of behavioral responses controlled by a drug-associated environment have remained poorly understood. The present study used a conditioning procedure to assess the roles of BDNF, Drd3, and their interactions in the NAc in the expression of morphine-induced context-specific locomotor sensitization. We showed that the expression of locomotor sensitization in the morphine-paired environment was accompanied by significantly increased expression of Drd3 mRNA and BDNF mRNA and protein levels. Both sensitized locomotion in morphine-paired rats and enhanced Drd3 mRNA were suppressed by intra-NAc infusion of anti-tyrosine kinase receptor B (TrkB) IgG. Furthermore, intra-NAc infusion of the Drd3-selective antagonist SB-277011A significantly decreased the expression of context-specific locomotor sensitization and upregulated BDNF mRNA. Altogether, these results suggest that BDNF/TrkB signaling and activation of Drd3 in the NAc are required for the expression of morphine-induced context-specific locomotor sensitization.     

A new buprenorphine analogy, thenorphine, inhibits morphine-induced behavioral sensitization in mice

AIM: To investigate effects of thenorphine, a new compound of partial agonist of μ-opioid receptor, on the loco-motor activity and the behavioral sensitization to morphine in mice. METHODS: Locomotor activity was observed after administration of thenorphine or co-administration of thenorphine and morphine in mice. Mice were induced behavioral sensitization to morphine by intraperitoneal injection of 20 mg/kg morphine once daily for 7 d. Thenorphine was co-administrated with morphine to observe the effects of thenorphine on the development, transfer and expression of morphine-induced behavioral sensitization. RESULTS: A single dose of thenorphine (0.0625, 0.25, and 1.0 mg/kg) could dose-dependently inhibit the locomotor activity in mice (P<0.05), repeated administrations of thenorphine, however, were not able to induce locomotor sensitization, but induced tolerance. Pretreatment with thenorphine 30 min prior to morphine effectively inhibited the psychomotor effect of morphine in mice (P<0.01). Co-adminis     

Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA

The conditionability of increases in locomotor activity induced by morphine administration into the ventral tegmental area was studied in rats. Morphine produced a clear increase in locomotor activity that was reversed by the opiate receptor blocker, naloxone, and blocked by the neuroleptic, pimozide, suggesting the mediation of this effect by the ascending mesolimbic dopamine system. The increase in locomotor activity showed sensitization with repeated morphine administrations and this sensitization was found to be specific to the environment in which morphine was administered. Conditioning tests also revealed that, in the absence of morphine, increased locomotor activity was elicited by the administration environment. Pimozide blocked the development of the conditioned sensitization. These data demonstrate that a learned association developed between this excitatory action of morphine and the administration environment. These results have important implications for the role of conditioning factors in relapse to drug use and may provide an explanation for conditioning data obtained when morphine is administered systemically.     

Behavioural sensitization in mice induced by morphine-glucuronide metabolites

Sensitization is thought to be involved in central aspects of drug addiction. Both morphine-3-glucuronid (M3G) and morphine-6-glucuronid (M6G) are rapidly formed in high concentrations shortly after heroin and morphine consumption. Their role in the development of sensitization has not previously been studied. In our study, mice received three injections of M6G or morphine at six day intervals. M6G induced locomotor sensitization comparable to morphine as early as the first injection. In a second experiment two injections of M6G or morphine were given, separated by 6, 12, 18, 24 or 30 days. A sensitized response was observed for both morphine and M6G up to 18 days after the first injection. In a third experiment with two injections, the first with M6G and the second with morphine, or the opposite sequence, M6G did not induce cross-sensitization to morphine although morphine induced cross-sensitization to M6G. Finally, pretreatment with M3G induced sensitization of morphine locomotor activity but not M6G. In conclusion M6G induced long-lasting sensitization similar but not identical to morphine. M3G was shown to sensitize morphine induced locomotor activity in a similar way to morphine pretreatment. This suggests that morphine-glucuronide metabolites may play a role in the development of addiction to morphine.     

Pharmacological action ofPanax Ginseng on the behavioral toxicities induced by psychotropic agents

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (mu-receptors) and mouse vas deferens (delta-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/ delta-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.