Biomedical subjects

M Funada

Publications and source records attributed to M Funada.

At least 19 recordsLinked to original sources

PubMed2004

Profiling of methamphetamine-induced modifications of gene expression patterns in the mouse brain.

Recently described DNA microarray technology allows parallel screening of expression patterns and regulation of hundreds of thousands of genes. In the present study, we used a microarray to examine the gene expressions in the midbrains of mice sacrificed 24 h after completion of a 7-day treatment period consisting of a once-daily treatment with saline (SS), saline followed by a single 2 mg/kg of body weight dose of methamphetamine (METH) (S-METH), or repeated 2 mg/kg METH doses (M-METH) that produced sensitization and place preference (rewarding effect). We used the commercially available cDNA microarray. Approximately 80% of the assessed transcripts in the total brain reached the Affymetrix criteria for "present" and "changed," as well as displaying > or =1.5-fold differences in hybridization intensity difference values in a comparison of SS data to S-METH or M-METH data. S-METH gene expression changes were observed in both up- and down-regulation, with 13 transcripts upregulated and 13 downregulated, whereas the majority of M-METH gene expression changes were observed in down-regulation, with 5 transcripts upregulated and 21 downregulated. We identified several genes that altered expression in both the S-METH and M-METH groups: a transcription factor gene, cellular stress/molecular chaperones, and a cellular regulatory gene.

Animals↗

PubMed2001

Involvement of corticotropin-releasing factor receptor subtype 1 in morphine withdrawal regulation of the brain noradrenergic system.

Effects of pretreatment with the selective corticotropin-releasing factor (CRF) subtype 1 (CRF(1)) receptor antagonist, 2-(N-(2-methylthio-4-isopropylphenyl)-N-ethyl-amino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) on the behavioral and biochemical changes after naloxone-precipitated morphine withdrawal were examined in ICR mice. Mice were chronically treated with morphine (8-45 mg/kg) for 5 days. Naloxone (3 mg/kg, s.c.) precipitated jumping, diarrhea, and body weight loss in morphine-dependent mice. In addition, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and noradrenaline turnover (MHPG/noradrenaline) levels in the cerebral cortex were increased following naloxone challenge in morphine-dependent mice. However, 5-hydroxytriptamine turnover did not alter the increase following naloxone challenge in morphine-dependent mice. Pretreatment with CRA1000 (20 mg/kg, i.p.) attenuated the incidence of withdrawal signs and naloxone-precipitated increases in noradrenaline turnover. These results suggest that the activation of CRF(1) receptor may play an important role in the elevation of noradrenaline transmission, but not in 5-hydroxytriptamine transmission, in the cerebral cortex, which projects from the locus coeruleus during morphine withdrawal.

Animals↗

PubMed2001

Differential effects of psychological stress on activation of the 5-hydroxytryptamine- and dopamine-containing neurons in the brain of freely moving rats.

We investigated the effects of psychological stress, lacking direct physical stimulus, on the release of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the basolateral nucleus of the amygdala (BLA) and the dorsal raphe nuclei (DRN) in the rat using the in vivo microdialysis technique with dual probes, one in each region of the same animals. Psychological stress was employed using the communication box paradigm. Psychological stress for 1 h significantly increased dialysate 5-HT levels in the DRN and the BLA. Psychological stress-induced 5-HT release in the BLA was significantly greater than those in the DRN, indicating that modifications of the serotonergic neurons in the BLA are more sensitive to psychological stress than are those of the DRN. Psychological stress also increased DA release in the BLA, while the dialysate DA levels in the DRN were unchanged. These results suggest that psychological stress preferentially activates ascending serotonergic neurons from the DRN to the BLA but not those of dopaminergic neurons. Furthermore, our findings indicate that both the serotonergic neurons and the dopaminergic neurons in the BLA may have a distinct role to play in the neuronal responses to psychological stress.

Amygdala↗

PubMed2001

Regulations of opioid dependence by opioid receptor types.

Three major types of opioid receptors, designated mu, delta, and kappa, are widely expressed in the CNS. Development of selective receptor ligands and recent cloning of each receptor have contributed greatly to our increasing knowledge of the neuropharmacological profile of each opioid receptor type. It is of interest to note that they include noncompetitive and allosteric interactions among their types. This review focuses on the functional interaction among these opioid receptor types that contribute to opioid dependence. Various studies provide arguments to support substantial roles for mu-opioid receptors and the possible involvement of delta-opioid receptors in the development of physical and psychological dependence on morphine. Noradrenergic transmission originating in the locus coeruleus is most likely to play the primary causal role in the expression of physical dependence on morphine. In contrast, many studies have pointed to the mesolimbic dopaminergic pathway projecting from the ventral tegmental area to the nucleus accumbens as a critical site for the initiation of psychological dependence on opioids. It is noteworthy as the broad existence of opposing interactions between mu/delta- and kappa-receptors in the brain. The activation of kappa-receptors leads to the suppression of unpleasant mu/delta-mediated side effects such as the rewarding effect. Considering the functional interaction among opioid receptor types, the co-administration of morphine-like compounds with kappa-receptor agonists may constitute a preferable and superior approach to the treatment of pain with fewer side effects.

Adrenergic Agonists↗

PubMed2001

Mu opiate receptor gene dose effects on different morphine actions: evidence for differential in vivo mu receptor reserve.

Homozygous transgenic knockout mice without mu-opioid receptors lack morphine-induced antinociception, locomotion, tolerance, physical dependence, and reward. mu receptors thus appear to play central roles in these morphine actions. Different levels of mu receptor expression are found in different humans and in different animal strains. In vitro studies indicate that some morphine responses persist after inactivation of as many as 90% of the initial mu receptor complement, while others are attenuated after inactivating many fewer receptors. Varying levels of mu receptor reserve could thus exist in different mu-expressing neuronal populations in vivo. Heterozygous mu receptor knockout mice express half of wild-type mu receptor levels. Tests of morphine actions in these mice reveal evidence for differing mu receptor reserves in brain circuits that mediate distinct opiate effects. Heterozygotes display attenuated locomotion, reduced morphine self-administration, intact tolerance, rightward shifts in morphine lethality dose/effect relationships, and variable effects on place preference compared to wild-type mice. They demonstrate full physical dependence, as measured by naloxone-precipitated abstinence following five days of morphine administration. Neuroadaptive changes in sites other than mu receptors could be involved in some of these results. Nevertheless, these data document substantial influences that individual differences in levels of mu receptor expression could exert on distinct opiate drug effects. They support the idea that functional mu receptor reserve differs among the diverse neuronal populations that mediate distinct properties of opiate drugs.

Animals↗

PubMed2000

Dynorphin A (2-17) attenuates the unconditioned but not the conditioned effects of opiate withdrawal in the rat.

OBJECTIVES: An unbiased place preference conditioning procedure was used to examine the influence of the non-opioid peptide, dynorphin A 2-17 (DYN 2-17), upon the conditioned and unconditioned effects of opiate withdrawal in the rat. METHODS: Rats were implanted SC with two pellets containing 75 mg morphine or placebo. Single-trial place conditioning sessions with saline and the opioid receptor antagonist naloxone (0.1-1.0 mg/kg; SC) commenced 4 days later. Ten minutes before SC injections, animals received an IV infusion of saline or DYN 2-17 (0.1-5.0 mg/kg). Additional groups of placebo- and morphine-pelleted animals were conditioned with saline and DYN 2-17. During each 30-min conditioning session, somatic signs of withdrawal were quantified. Tests of place conditioning were conducted in pelleted animals 24 h later. RESULTS: Naloxone produced wet-dog shakes, body weight loss, ptosis and diarrhea in morphine-pelleted animals. Morphine-pelleted animals also exhibited significant aversions for an environment previously associated with the administration of naloxone. These effects were not observed in placebo-pelleted animals. DYN 2-17 pretreatment resulted in a dose-related attenuation of somatic withdrawal signs. However, conditioned place aversions were still observed in morphine-pelleted animals that had received DYN 2-17 in combination with naloxone. Furthermore, the magnitude of this effect did not differ from control animals. CONCLUSIONS: These data demonstrate that the administration of DYN 2-17 attenuates the somatic, but not the conditioned aversive effects of antagonist-precipitated withdrawal from morphine in the rat. Differential effects of this peptide in modulating the conditioned and unconditioned effects of opiate withdrawal are suggested.

Animals↗

PubMed1999

Visceral chemical nociception in mice lacking mu-opioid receptors: effects of morphine, SNC80 and U-50,488.

Writhing responses to intraperitoneal acetic acid administration and their modulation by mu-, kappa- and delta-opioid receptor agonists were compared in wild-type and mu-opioid receptor knockout mice. Unpretreated homozygous knockout mice displayed less writhing than wild-type mice. U-50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl]-benze neacetamide]) reduced writhing responses in wild-type and knockouts. Morphine and SNC80 [(+)-4-[9-alpha-R)-alpha-(2S,5RO-4-allyl-2,5-dimethyl-1-piperaziny l)-3-methoxybenzyl]-N,N-diethylbenzamide] were effective in wild-type mice but ineffective in knockouts. Mu-opioid receptors appear to play important roles in responses to this visceral nociceptive stimulus and its modulation by mu- and delta-opioid receptor agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1997

rGbeta1: a psychostimulant-regulated gene essential for establishing cocaine sensitization.

Repeated doses of cocaine or amphetamine lead to long-lasting behavioral manifestations that include enhanced responses termed sensitization. Although biochemical mechanisms that underlie these manifestations currently remain largely unknown, new protein synthesis has been implicated in several of these neuroadaptive processes. To seek candidate biochemical mechanisms for these drug-induced neuroplastic behavioral responses, we have used an approach termed subtracted differential display (SDD) to identify genes whose expression is regulated by these psychostimulants. rGbeta1 is one of the SDD products that encodes a rat G-protein beta subunit. rGbeta1 expression is upregulated by cocaine or amphetamine treatments in neurons of the nucleus accumbens shell region, a major center for psychostimulant effects in locomotor control and behavioral reward. Antisense oligonucleotide treatments that attenuate rGbeta1 expression in regions including the nucleus accumbens abolish the development of behavioral sensitization when they are administrated during the repeated cocaine exposures that establish sensitization. These treatments fail to alter acute behavioral responses to cocaine, and they do not block the expression of cocaine sensitization when it is established before oligonucleotide administrations. Full, regulated rGbeta1 expression is a biochemical component essential to the establishment of a key consequence of repeated cocaine administrations, sensitization.

Amino Acid Sequence↗

PubMed1997

The mu-opioid receptor is necessary for [D-Pen2,D-Pen5]enkephalin-induced analgesia.

Interactions between delta-opioid receptors and morphine-preferring mu-opioid receptor subtypes have been suggested. Availability of transgenic mu-opioid receptor knockout mice allows assessment of mu-opioid receptor roles in the analgesia produced by the classical delta-opioid receptor agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) in hot-plate and tail-flick tests. DPDPE analgesia was dramatically reduced in mu-opioid receptor knockout mice in a gene-dose-dependent fashion. The analgesia induced by this classic delta-opioid receptor agonist depends on intact mu-opioid receptors, suggesting that selective delta-opioid receptor drugs may require mu-opioid receptor occupancies for full efficacy.

Analgesia↗

PubMed1997

Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia.

Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. mu, delta, and kappa opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in drug-free and morphine-treated states have not been clear, however. We produced homologous, recombinant mu, opiate receptor, heterozygous and homozygous knockout animals that displayed approximately 54% and 0% of wild-type levels of mu receptor expression, respectively. These mice expressed kappa receptors and delta receptors at near wild-type levels. Untreated knockout mice displayed shorter latencies on tail flick and hot plate tests for spinal and supraspinal nociceptive responses than wild-type mice. These findings support a significant role for endogenous opioid-peptide interactions with mu opiate receptors in normal nociceptive processing. Morphine failed to significantly reduce nociceptive responses in hot plate or tail flick tests of homozygous mu receptor knockout mice, and heterozygote mice displayed right and downward shifts in morphine analgesia dose-effect relationships. These results implicate endogenous opioid-peptide actions at mu opiate receptors in several tests of nociceptive responsiveness and support mu receptor mediation of morphine-induced analgesia in tests of spinal and supraspinal analgesia.

Analgesia↗

PubMed1996

Role of delta-opioid receptors in mediating the aversive stimulus effects of morphine withdrawal in the rat.

An unbiased place preference conditioning procedure was used to examine the role of delta-opioid receptors in mediating the aversive effects of opioid withdrawal. Rats were implanted s.c. with two pellets each containing placebo or 75 mg morphine. Single-trial conditioning sessions with saline and the opioid receptor antagonists naloxone (0.001-1.0 mg/kg, s.c.), naltrindole (0.01-3.0 mg/kg, s.c.) or naltriben (0.01-3.0 mg/kg, s.c.) commenced 4 days later. During these conditioning sessions, physical signs of withdrawal were also quantified. Tests of conditioning were conducted on day 5. Naloxone in doses of 0.01-1.0 mg/kg produced significant conditioned place aversions in morphine-implanted animals. A dose of 0.01 mg/kg produced few physical withdrawal signs whereas higher doses resulted in marked wet dog shakes, body weight loss ptosis and diarrhea. No such effects were observed in control (placebo-implanted) animals. Administration of the selective delta-opioid receptor antagonists naltrindole and naltriben produced dose-related place aversions in morphine-implanted animals. The magnitude of these effects did not differ from that observed with naloxone. The minimum effective doses of naltrindole and naltriben were 0.1 mg/kg. Doses of 0.1-1.0 mg/kg produced few, if any, somatic signs of withdrawal whereas higher doses of these antagonists only produced diarrhea and wet-dog shakes. Other withdrawal signs were absent. In contrast to the opioid receptor antagonists tested, the dopamine D1 receptor antagonist SCH23390 failed to produced conditioned place aversions or physical signs of withdrawal in morphine-pelleted animals. These data demonstrate that the selective blockade of either delta- or mu-opioid receptors is sufficient to induce conditioned aversive effects in morphine-dependent animals. They also indicate that physical symptoms associated with precipitated morphine withdrawal differ depending upon the opioid receptor antagonist employed.

Animals↗

PubMed1996

Diazepam pretreatment suppresses morphine withdrawal signs in the mouse.

The effect of diazepam on the development of physical dependence on morphine and on the naloxone-precipitated increase in cortical NA turnover were investigated in mice. Co-administration of diazepam (1-4 mg/kg, i.p.) during chronic morphine treatment suppressed the expression of naloxone (3 mg/kg, s.c.)-precipitated withdrawal signs (jumping, exploratory rearing and weight loss). However, a single injection of diazepam (4 mg/kg, i.p.) in morphine-dependent mice did not affect the expression of naloxone-precipitated withdrawal signs. The 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) level and noradrenaline (NA) turnover (MHPG/NA) in the cerebral cortex were increased by naloxone (3 mg/kg) challenge. These increases in the cortical MHPG level and NA turnover were significantly prevented by co-administration of diazepam (4 mg/kg, i.p.) during chronic morphine treatment. These findings suggest that the co-administration of diazepam during chronic morphine treatment may prevent some neurochemical changes in the central noradrenergic system during chronic morphine treatment, and may suppress the development of physical dependence on morphine. Therefore, the inhibitory action of GABA via benzodiazepine binding sites may play an important role in the development of physical dependence on morphine.

Adrenergic alpha-Agonists↗

PubMed1995

Blockade of morphine-induced place preference by diazepam in mice.

The effects of diazepam on morphine-induced place preference were examined in mice. Pretreatment with diazepam (2 mg/kg i.p.) 30 min prior to morphine injection significantly abolished the morphine (5 mg/kg s.c.)-induced place preference, and this effect of diazepam was antagonized by pretreatment with flumazenil. In addition, pretreatment with diazepam prevented the morphine (5 mg/kg s.c.)-induced increase in dopamine turnover in the limbic forebrain. These results suggest that pretreatment with diazepam may suppress the rewarding effects of morphine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Adrenalectomy potentiates the morphine--but not cocaine-induced place preference in rats.

The conditioned place preference paradigm is commonly used to study the reinforcing properties of various drugs. In the present study, the effect of adrenalectomy (ADX) on the morphine-induced place preference was examined in rats. Morphine produced a significant preference for the drug-associated place in sham-operated (sham) and ADX rats. In sham rats, only the highest dose of morphine (8 mg/kg, i.p.) produced a significant preference, while in ADX rats, lower doses of morphine (1 and 2 mg/kg, i.p.) produced a significant preference for the drug-associated place. Furthermore, the morphine-induced place preference was blocked by the dopamine D1 antagonist SCH23390 in both sham and ADX rats. On the other hand, the cocaine-induced place preference was not affected by ADX. In the present study, we found that ADX potentiates the reinforcing effect induced by morphine, but not that induced by cocaine, which suggests that the enhancement by ADX may be due to a change in opioid receptors, morphine metabolism and/or some other cause, but not a change in dopamine receptors.

Adrenalectomy↗

PubMed1995

The D3-receptor agonist (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) attenuates morphine-induced hyperlocomotion in mice.

The effects of the D3-agonist (+/-)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) on morphine-induced hyperlocomotion were investigated in mice. 7-OH-DPAT (0.01-0.3 mg/kg s.c.) alone did not produce a significant locomotor activity in mice. Treatment with low doses of 7-OH-DPAT (0.1 and 0.3 mg/kg s.c.) attenuated morphine (10 and 20 mg/kg s.c.)-induced hyperlocomotion. The significant morphine-induced increase in dopamine (DA) metabolite levels, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the limbic forebrain (nucleus accumbens and olfactory tubercle) was suppressed by 7-OH-DPAT. These results suggest that activation of the D3-receptor in the mesolimbic dopamine system may attenuate the expression of morphine-induced hyperlocomotion.

Animals↗

PubMed1994

Attenuation of the discriminative stimulus properties of cocaine by delta-opioid receptor antagonists.

The effects of selective delta-opioid receptor antagonists on the discriminative stimulus properties of cocaine were examined in rats trained to discriminate between cocaine (10 mg/kg) and saline. Pretreatment with naltrindole (a non-selective delta-opioid receptor antagonist) and naltriben (a selective delta 2-opioid receptor antagonist), but not 7-benzylidenenaltrexone (a selective delta 1-opioid receptor antagonist), significantly attenuated the discriminative stimulus properties of cocaine. Naltrindole and naltriben attenuated the discriminative stimulus properties of doses of cocaine lower than the training dose. Although the effects produced by the training dose were not changed, our finding may have some bearing on the relative importance of the role of delta-opioid (especially delta 2-opioid) receptors in the discriminative stimulus properties of cocaine.

Animals↗

PubMed1994

Effects of diabetes on spontaneous locomotor activity in mice.

Spontaneous locomotor activity in diabetic mice was significantly greater than that in non-diabetic mice. Haloperidol and SCH23390, a selective dopamine D1-receptor antagonist, significantly reduced spontaneous locomotor activity in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity in diabetic mice was also reduced by pretreatment with naltrindole, a selective delta-opioid receptor antagonist, and 7-benzylidenenaltrexone, a selective delta1-opioid receptor antagonist. The rate of dopamine turnover in the limbic forebrain in diabetic mice was significantly higher than that in non-diabetic mice. These findings suggest that the enhanced spontaneous locomotor activity in diabetic mice may result from increased dopamine neurotransmission, which might be due to an increase in dopamine release in mesolimbic dopamine systems. The increased dopamine neurotransmission in diabetic mice may also be due to the up-regulation of delta-opioid receptor-mediated functions.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

The role of dopamine D1-receptors in morphine-induced hyperlocomotion in mice.

The effects of treatment with dopamine (DA) D1-agonist SKF38393 and D2-agonist quinpirole on morphine-induced hyperlocomotion were investigated in mice. Morphine-induced hyperlocomotion was increased by approximately 2.0-fold in SKF38393 (10 nmol, i.c.v.)-treated mice. Pretreatment with SCH23390 antagonized the enhancing effect of SKF38393. In contrast, pretreatment with quinpirole (10 nmol, i.c.v.) reduced morphine-induced hyperlocomotion. Morphine significantly increased DA metabolite levels, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the limbic forebrain (nucleus accumbens and olfactory tubercle). This elevation of DA metabolites by treatment with morphine was not modified by the co-administration of SKF38393. These results suggest that the activation of D1-receptors in the limbic forebrain may enhance the expression of morphine-induced hyperlocomotion.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗