Akiyoshi Saitoh

Antinociceptive effects of the selective non-peptidic δ-opioid receptor agonist TAN-67 in diabetic mice

The antinociceptive potencies of 2-methyl-4 alpha alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12 alpha alpha-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), a non-peptidic delta-opioid receptor agonist, were examined using the acetic acid abdominal constriction test and the tail-flick test in diabetic mice. TAN-67, at doses of 3-100 mg/kg, s.c. [corrected], produced a marked and dose-dependent inhibition of the number of acetic acid-induced abdominal constrictions in both non-diabetic and diabetic mice. The antinociceptive effect of TAN-67 in the acetic acid abdominal constriction test in diabetic mice was greater than that in non-diabetic mice. Indeed, the ED50 (95% confidence limits) value of TAN-67 for the inhibition of acetic acid-induced abdominal constrictions in diabetic mice (6.0 (3.5-10.5) mg/kg) was significantly lower than that in non-diabetic mice (31.4 (14.2-69.4) mg/kg). The antinociceptive effect of TAN-67 was not antagonized by pretreatment with either beta-funaltrexamine, a selective mu-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist. When 7-benzylidenenaltrexone (0.3 mg/kg, s.c.), a selective delta 1-opioid receptor antagonist, was administered 10 min before treatment with TAN-67, the antinociceptive effect of TAN-67 was significantly antagonized. However, naltriben, a selective delta 2-opioid receptor antagonist, had no significant effect on the antinociceptive effect of TAN-67. Furthermore, in the tail-flick test, TAN-67 at doses of 3-30 mg/kg, s.c. [corrected], also produced a marked and dose-dependent antinociceptive effect in diabetic mice, but not in non-diabetic mice. In conclusion, TAN-67 produced an antinociceptive effect through the activation of delta 1-opioid receptors. Furthermore, the results of this study support our hypothesis that mice with diabetes are selectively hyperresponsive to delta 1-opioid receptor-mediated antinociception.

Role of δ-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats

RationaleRecent studies have shown that endogenous opioid systems are associated with the regulation of emotional responses. In particular, it has been reported that δ-opioid receptors act naturally to inhibit stress and anxiety.ObjectiveThe present study was designed to examine the possible involvement of opioid δ-receptor subtypes in the anxiety-related behavior in the elevated-plus-maze test.MethodsSix-week-old male Lewis rats were used. The total numbers of visits to the closed and open arms and the cumulative time spent and visits in the open arms were determined. Plasma corticosterone levels were measured by enzyme immunoassay.ResultsNaltrindole (NTI), a δ-opioid receptor antagonist (3xa0mg/kg s.c.), induced a significant decrease in the percentages of time spent and visits in the open arms. Naltriben (NTB), a δ2-opioid receptor antagonist (3xa0mg/kg s.c.), but not 7-benzylidenenaltrexone, a δ1-opioid receptor antagonist, produced similar anxiety-related behaviors in the elevated plus-maze. These effects of NTI and NTB were antagonized by pretreatment with (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), a δ-opioid receptor agonist. Furthermore, after exposure to the elevated plus-maze, the maximal increase in the plasma corticosterone level in NTI-treated rats was clearly higher than that in vehicle-treated rats. However, when NTI and SNC80 were coadministered, higher levels of plasma corticosterone were not seen after exposure to the elevated plus-maze.ConclusionThese results suggest that endogenous δ2-opioid-receptor-mediated systems are involved in the regulation of anxiety-related behaviors and might play a physiologically important role in the regulation of adrenocortical activity.

Validity of the Patient Health Questionnaire (PHQ)-9 and PHQ-2 in general internal medicine primary care at a Japanese rural hospital: a cross-sectional study

OBJECTIVEnTwo depression screening tools, Patient Health Questionnaire (PHQ)-9 and PHQ-2, have not had their validity examined in general internal medicine settings in Japan. We examined the validity of these screening tools.nnnMETHODSnA total of 598 outpatients of an internal medicine clinic in a rural general hospital were enrolled consecutively and stratified by PHQ-9 score. Seventy-five patients randomly selected and 29 patients whose results from the PHQ-9 were considered to be positive for depressive disorder were then interviewed with a semistructured interview, the Mini International Neuropsychiatric Interview. We calculated diagnostic accuracy of the PHQ-9 and PHQ-2 to detect major depression and that of the suicidality item of the PHQ-9 to detect suicidality using sampling weights with multiple imputations.nnnRESULTSnSensitivity and specificity for depression were 0.86 and 0.85, respectively, for the PHQ-9 with cutoff points of 4/5, and 0.77 and 0.95, respectively, for the PHQ-2 with cutoff points of 2/3. Sensitivity and specificity of the suicidality item of the PHQ-9 were 0.70 and 0.97, respectively.nnnCONCLUSIONnIn internal medicine clinics in Japanese rural hospitals, the PHQ-2 with an optimal cutoff point for each setting plus the suicidality item of the PHQ-9 can be recommended to detect depression without missing suicidality.

Supraspinal δ1-opioid receptor-mediated antinociceptive properties of (−)-TAN-67 in diabetic mice

Abstract The antinociceptive potencies of the enantiomorphs of TAN-67 (2-methyl-4 a α-(3-hydroxyphenyl)-1,2,3,4,4 a ,5,12,12 a α-octahydro-quinolino[2,3,3,– g ]isoquinoline), (−)-TAN-67 and (+)-TAN-67, given intracerebroventricularly (i.c.v.) on the antinociceptive response were studied in streptozotocin-induced diabetic mice using the tail-flick test. (−)-TAN-67 at doses of 3–10 μg given i.c.v. produced dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice. The antinociceptive effect of (−)-TAN-67 in the tail-flick test in diabetic mice was greater than that in non-diabetic mice. The antinociceptive effect of (−)-TAN-67 was not antagonized by pretreatment with either β-funaltrexamine, a selective μ-opioid receptor antagonist, or nor-binaltorphimine, a selective κ-opioid receptor antagonist. When 7-benzylidenenaltrexone, a selective δ 1 -opioid receptor antagonist, was administered 10 min before treatment with (−)-TAN-67, the antinociceptive effect of (−)-TAN-67 was significantly antagonized. However, naltriben, a selective δ 2 -opioid receptor antagonist, had no significant effect on the antinociceptive effect of (−)-TAN-67. On the other hand, in the tail-flick test, (+)-TAN-67 at doses of 3–30 μg given i.c.v. did not produce dose-dependent inhibition of the tail-flick response in either non-diabetic or diabetic mice. In conclusion, (−)-TAN-67, but not its enantiomer (+)-TAN-67, produced an antinociceptive effect through the activation of δ 1 -opioid receptors. ©xa01997 Elsevier Science B.V. All rights reserved.

Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats

RationaleIt has been reported that many of the behavioral and serotonergic neuronal changes observed in olfactory bulbectomy (OBX) were improved by subchronic administration of a variety of antidepressants.ObjectiveWe examined the effects of subchronic treatment with milnacipran, a dual serotonin and noradrenaline reuptake inhibitors (SNRIs) and fluvoxamine, selective serotonin reuptake inhibitors (SSRI) in the OBX-induced hyperemotional behaviors and tryptophan hydroxylase (TPH), rate-limiting enzyme of 5-HT.Materials and methodsThe olfactory bulbs were removed by suction. Drugs were administered p.o. once daily for 8xa0days beginning 14xa0days post-surgery. The hyperemotionality behaviors of OBX rats were measured by rating scale and in the elevated plus-maze test.ResultsOBX rats, after milnacipran or fluvoxamine treatment, showed significant decrease in the score of hyperemotional responses on 7th day as compared with vehicle-treated OBX rats. In addition, milnacipran and fluvoxamine in OBX rats respectively produced a significant increase in the percentage of time spent in and number of entries into open arms in the elevated plus maze test. Furthermore, when 5-HTnergic neuronal function was examined using antibodies against tryptophan hydroxylase (TPH) following the behavioral tests, fluvoxamine significantly reversed the loss of TPH-positive cells produced by OBX in the dorsal raphe.ConclusionWe demonstrated that chronic treatment with milnacipran or fluvoxamine was effective to improve both the hyperemotional behavior and the loss of TPH-positive cells seen in OBX rats.

Riluzole rapidly attenuates hyperemotional responses in olfactory bulbectomized rats, an animal model of depression.

Growing evidence indicates that the glutamatergic neurotransmitter system is central to the neurobiology and treatment of depression. Riluzole, a drug currently used to slow the progression of amyotrophic lateral sclerosis (ALS), directly affects the glutamatergic system. In this study, we investigated the effects of riluzole in olfactory bulbectomy (OBX) rats, an animal model of depression. The olfactory bulbs in rats were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed significant increases in emotionality responses. Single (1st day administration) and subchronic (7th day administration) riluzole treatment (1-10 mg/kg, po) significantly and dose-dependently reduced hyperemotional responses in OBX rats. Both single and subchronic riluzole treatment (10 mg/kg, po) had no significant effects on the emotional responses in sham operated rats. In addition, we demonstrated that single riluzole treatment (10 mg/kg, po) significantly decreased extracellular glutamate levels in medial prefrontal cortex of OBX rats by in vivo microdialysis. We provide the first experimental evidence that riluzole rapidly attenuated hyperemotional responses in OBX rats, an animal model of depression.

Buprenorphine exerts its antinocicepttve activity via μ1-opioid receptors

The mechanism of the antinociceptive effect of buprenorphine was assessed by administering selective mu-, mu1--, delta- and kappa-opioid receptor antagonists in mice. Intraperitoneal administration of buprenorphine, at doses of 0.3 to 3 mg/kg, produced dose-dependent antinociception in the tail-flick test. The antinociceptive activity of buprenorphine did not result from the activation of kappa- or delta-opioid receptors, since treatment with either nor-binaltorphimine, a selective kappa-opioid receptor antagonist, or naltrindole, a selective delta-opioid receptor antagonist, was completely ineffective in blocking buprenorphine-induced antinociception. However, the antinociceptive effect of buprenorphine was significantly antagonized by beta-funaltrexamine, a selective mu-opioid receptor antagonist. Moreover, selective mu1-opioid receptor antagonist, naloxonazine and naltrexonazine, also significantly antagonized the antinociceptive effect of buprenorphine. Co-administration of kappa- and delta-opioid receptor antagonist with the mu-opioid receptor antagonists had no significant effect on the antagonistic profiles of the mu-opioid receptor antagonists on the antinociceptive effect of buprenorphine. These results suggest that buprenorphine acts selectively at mu1-opioid receptors to induce antinociceptive effects in mice.

Involvement of dopamine D2 receptor-mediated functions in the modulation of morphine-induced antinociception in diabetic mouse

The effects of the dopamine agonists and antagonists on morphine-induced antinociception in diabetic mice were studied. The antinociceptive effect of morphine (5 mg/kg, s.c.) in diabetic mice was significantly less than that in non-diabetic mice. The antinociceptive effect of morphine in diabetic mice, but not that in non-diabetic mice, was significantly enhanced following pretreatment with sulpiride, a selective dopamine D2 antagonist, (30 mg/kg, s.c.). Pretreatment with quinpirole, a selective dopamine D2 agonist, (100 nmol, i.c.v.), markedly increased the antinociceptive effect of morphine in diabetic mice, but not in non-diabetic mice. There was no significant difference in the antinociceptive effect of morphine (5 mg/kg, s.c.) between the quinpirole-treated diabetic mice and saline-treated non-diabetic mice. A higher dose of quinpirole (300 nmol, i.c.v.) had no significant effect on morphine-induced antinociception in diabetic mice. On the other hand, the antinociceptive effect of morphine was significantly reduced by pretreatment with quinpirole (300 nmol, i.c.v.) in non-diabetic mice. Quinpirole (100 and 300 nmol, i.c.v.) dose-dependently increased total locomotor activity in non-diabetic mice. In contrast, a lower dose of quinpirole (100 nmol, i.c.v.) significantly reduced spontaneous locomotor activity in diabetic mice, while a higher dose of quinpirole had no significant effect on the spontaneous locomotor activity. The dopamine turnover ratio in the limbic forebrain and midbrain in diabetic mice were significantly greater than those in non-diabetic mice. When mice were pretreated with quinpirole (100 and 300 nmol, i.c.v), this enhanced dopamine turnover ratio was not observed in either the limbic forebrain or the midbrain of diabetic mice. These findings suggest that the attenuation of morphine-induced antinociception and dopamine D2 receptor-mediated function in diabetic mice may somehow be related.

Riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines.

In this study, we investigated the anxiolytic-like effect of riluzole using three different innate anxiety models in rats. In the elevated plus-maze test, riluzole significantly increased the time spent in, and entries into, the open arm after 60xa0min administration. This finding was supported by results obtained from light/dark and open-field tests. The magnitude of the anxiolytic-like effects of riluzole in each of the behavioral models was similar to those produced by a benzodiazepine, diazepam, suggesting that riluzole has a robust anxiolytic-like activity in rats. To clarify the involvement of sodium channels in this anxiolytic activity, we examined the effect of a co-administered sodium channel activator, veratrine. The anxiolytic-like action of riluzole was diminished by veratrine in the elevated plus-maze, light/dark and open-field tests. Based on these results, it is suggested that the anxiolytic mechanism of riluzole is clearly distinct from that of diazepam. In addition, to examine whether riluzole directly and non-selectively affected the GABA(A)-benzodiazepine receptor complex, we performed three behavioral tests (footprint analysis, Y-maze test and the ethanol-induced sleeping time test) that are closely related to the GABA(A)-benzodiazepine pathways. In contrast to diazepam, riluzole produced no significant effects in these tests. Here, we provide the first report demonstrating that riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines.

Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model.

The responses of olfactory bulbectomized (OBX) rats to antidepressant treatment are similar to those of depressed patients since chronic administration of an antidepressant reverses OBX-induced behavioral and physiological changes. Previously, using several animal models, it was demonstrated that single treatment with delta-opioid receptor agonists produced an antidepressant-like effect. This study examined the antidepressant effects resulting from subchronic exposure for 8 days to the delta-opioid receptor agonist SNC80 in an OBX rat model of depression. The olfactory bulbs were removed by suction. The emotionality of rats was measured by scoring their responses to given stimuli, i.e., attack, startle, struggle, and fight responses. The OBX rats chronically treated with vehicle for 7 days at 14 days following surgery showed a significant increase in emotionality score and a decrease in the time spent and entries in the open arm of a plus-maze. In the case of OBX rats, these changes were dose- and time-dependently reversed by chronic SNC80 treatment (1-10 mg/kg, s.c.) for 7 days, as same as desipramine (10 mg/kg, i.p.). Moreover, the concentration of 5-HT and its metabolite 5-HIAA in the frontal cortex, hippocampus, and amygdala were decreased in OBX rats, and these changes were also normalized by SNC80 treatment, rather than desipramine treatment. In addition, SNC80 also significantly reversed the loss of TH-positive cells produced by OBX in the dorsal raphe. In conclusion, we demonstrated that subchronic SNC80 treatment could completely reverse OBX-induced behavioral abnormalities and defects in serotonergic function.