Tohru Toyoshi

DAGO ([d-Ala2,N-Me-Phe4,Gly-ol]enkephalin) specifically reverses apomorphine-induced increase in rearing and grooming behaviors in the mouse

The effects of intracerebroventricular injections (10 microliters) of the mu-selective opioid peptide DAGO on apomorphine (0.1, 0.56, 1.0 and/or 3.0 mg/kg)-induced motor activity were investigated in the mouse using multi-dimensional behavioral analyses. A lower dose (0.1 mg/kg) of apomorphine failed to significantly affect motor activity, whilst higher doses (0.56, 1.0 and 3.0 mg/kg) of the drug produced a marked increase in linear locomotion, circling, rearing and/or grooming behaviors. DAGO (0.003 and 0.01 micrograms) did not significantly affect different behaviors. DAGO (0.01 micrograms) antagonized the apomorphine (1.0 mg/kg)-induced increase in behaviors such as rearing and grooming. However, DAGO (0.003 or 0.01 micrograms) did not affect behaviors induced by a 3.0 mg/kg dose of apomorphine. Furthermore, the effects of DAG]O on apomorphine-induced behaviors were fully reversed by treatment with the mu-selective alkylating agent beta-FNA (beta-funaltrexamine) (5.0 micrograms). These results suggest that mu opioid receptors play a principal role in the apomorphine-induced increase in rearing and grooming behaviors.

Multi-dimensional analysis of behavior in mice treated with the delta opioid agonists DADL (d-Ala2-d-Leu5-enkephalin) and DPLPE (d-Pen2-l-Pen5-enkephalin)

The effects of intracerebroventricular injection of the delta-selective opioid peptides, DADL (D-Ala2-D-Leu5-enkephalin) and DPLPE (D-Pen2-L-Pen5-enkephalin), on spontaneous locomotor activity were investigated in mice using multi-dimensional behavioral analysis, based upon a capacitance system. The analysers classified the movements into 9 sizes (1/1, 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128 and 1/256). Specific patterns of behavior were each registered on these sizes of movement. At 1.0 and 3.0 micrograms, DADL produced a significant increase in circling (1/4 size of movements) within 15 min after the start of measurements, while it produced a marked increase in linear locomotion (1/2 size), circling (1/4 size), rearing (1/16 size) and grooming (1/32, 1/64 and 1/128 sizes) within 15-30 min after the start. At 10.0 micrograms, DPLPE decreased linear locomotion (1/1 size) and conversely increased circling behavior (1/4 size) within 15 min after the start, whilst this peptide at 3.0 or 10.0 micrograms, produced a marked increase in linear locomotion (1/2 size), circling (1/4 size) and grooming (1/128 size) within 15-30 min after the start. The behavioral effects induced by DADL (3.0 micrograms) and DPLPE (10.0 micrograms) were completely reversed by naloxone (1.0 and 2.0 mg/kg). These results obtained with DPLPE, a delta-selective peptide and DADL, a less delta-selective peptide, indicate a common pattern of activity which was presumably delta receptor-mediated. However, one component (linear locomotion, at times immediately after administration of the peptide) did clearly differ between these two peptide analogues.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynorphin A(1–13) modulates apomorphine-induced behaviors using multidimensional behavioral analyses in the mouse

The effects of intracerebroventricular injection of dynorphin A(1-13) on apomorphine-induced behavioral changes were investigated in the mouse using multidimensional behavioral analyses based upon a capacitance system. Although lower doses (0.1 or 0.3 mg/kg) of apomorphine were without marked effects on behaviors, a 0.56 mg/kg dose of the drug evoked a significant increase in rearing behaviors. Furthermore 1.0 and 3.0 mg/kg doses of apomorphine produced a marked increment in linear locomotion, circling and rearing. Dynorphin A(1-13) (3.0 or 10.0 microgram) itself had no effects on behaviors. The apomorphine (0.56 and 1.0 mg/kg)-induced increase in rearing behaviors was clearly inhibited by treatment with dynorphin A(1-13) (3.0 and 10.0 microgram). Simultaneously, the marked increases in linear locomotion and circling were displayed by apomorphine (1.0 mg/kg) plus dynorphin A(1-13) (10.0 microgram). The effects of dynorphin A(1-13) (10.0 microgram) on the apomorphine (1.0 mg/kg)-induced increase in rearing were entirely reversed by the opioid antagonist Mr2266. These results suggest that the antagonistic effects of dynorphin A(1-13) on the apomorphine (1.0 mg/kg)-induced increase in rearing are mediated via opioid receptors, possibly K-sites.

Combination of a δ opioid receptor agonist but not a μ opioid receptor agonist with the D1-selective dopamine receptor agonist SKF 38393 markedly potentiates different behaviors in mice

The effects of intracerebroventricular injections of opioid peptides selective for mu or delta opioid receptors on behaviors induced by the D1 dopamine agonist SKF 38393 were investigated by using multi-dimensional behavioral analyses. A 10.0 mg/kg dose of SKF 38393 produced a marked increase in grooming behavior. The SKF 38393 (10.0 mg/kg)-induced increase in grooming behavior was clearly antagonized by SCH 23390 (0.03 mg/kg), a D1 dopamine antagonist, but not by S(-)-sulpiride (10.0 mg/kg), a D2 dopamine antagonist. [D-Ala2,MePhe4,Gly5-ol]enkephalin (DAMGO) (0.003 and 0.01 microgram), a mu-selective agonist, or [D-Pen2,L-Pen5]enkephalin (DPLPE) (0.3 or 1.0 microgram), a delta-selective agonist, failed to affect spontaneous behaviors. The combination of DPLPE (0.3 and 1.0 microgram) but not of DAMGO (0.003 and 0.01 microgram) with SKF 38393 (10.0 mg/kg) produced a marked increase in linear locomotion and circuling away from the side receiving the peptide, whereas grooming behavior was not affected. The effects induced by DPLPE (1.0 microgram) plus SKF 38393 (10.0 mg/kg) were fully reversed by the delta-selective opioid antagonist naltrindole (10.0 mg/kg), SCH 23390 (0.03 mg/kg) and S(-)-sulpiride (10.0 mg/kg). These findings suggest that delta but not mu opioid systems interact with D1 dopamine receptors, resulting in a marked increase in linear locomotion and contralateral circuling without causing marked changes in grooming behavior.

Dynorphin A(1–13) preferentially inhibits behaviors induced by the D2 dopamine agonist RU 24213 but not by the D1 dopamine agonist SK&F 38393

The effects of dynorphin A(1-13) on the D1 dopamine agonist SK&F 38393- and the D2 dopamine agonist RU 24213-induced behavioral alterations in the mouse were determined by using multidimensional behavioral analyses based upon a capacitance system. Although dynorphin A(1-13) (3.0 or 12.5 micrograms) alone did not produce any significant effects on behaviors, the peptide (12.5 micrograms) caused an inhibitory effect on the RU 24213 (3.0 mg/kg)-induced increase in behavioral patterns such as linear locomotion and circling except rearing and grooming behaviors. The antagonistic effects of dynorphin A(1-313) (12.5 micrograms) were fully reversed by the opioid antagonist M(r) 2266 (10.0 mg/kg). However, dynorphin A(1-13) (3.0 or 12.5 micrograms) failed to affect behaviors elicited by SK&F 38393 (10.0 mg/kg). These results suggest that dynorphin A(1-13) plays an inhibitory role in behaviors induced by the D2 dopamine agonist but not by the D1 dopamine agonist, possibly through the mediation of kappa-opioid receptors.

Systemic administration of dynorphin A(1–13) markedly inhibits different behavioural responses induced by cocaine in the mouse

The effects of systemic administration (i.p.) of dynorphin A(1-13) on the cocaine-induced behavioural alterations in the mouse were determined by using multi-dimensional behavioural analyses, based upon a capacitance system. A 1.0 mg/kg dose of cocaine did not influence behaviour, while increasing doses to 3-30 mg/kg produced a significant increment in the frequency of behaviour, such as linear locomotion, circling, rearing and grooming. Although a 1.0 mg/kg dose of dynorphin A(1-13) alone produced a significant decrease in grooming behaviour, larger doses (3.0 and 10.0 mg/kg) of the peptide failed to affect different behaviour. The cocaine (3.0 mg/kg)-induced increases in linear locomotion, circling and rearing behaviour were significantly inhibited by dynorphin A(1-13) (10.0 mg/kg). The inhibitory effects of dynorphin A(1-13) (10.0 mg/kg) were antagonized by the opioid antagonist Mr 2266 (5.6 mg/kg). It is thus possible that the systemic administration of dynorphin A(1-13) inhibits different behavioural responses induced by cocaine through the blood-brain barrier, although the instability of amino acid bonds or the relatively large molecular weight of dynorphin A(1-13), may result in the failure to demonstrate opioid activity by the peptide after systemic administration.

Multidimensional behavioral analyses show dynorphin A-(1–13) modulation of methamphetamine-induced behaviors in mice

The effects of intracerebroventricular (i.c.v.) injection of dynorphin A-(1-13) on methamphetamine-induced behavioral alterations in mice were determined by using multidimensional behavioral analyses. Methamphetamine (0.3, 1.0 and 3.0 mg/kg s.c.) produced a marked increase in linear locomotion, circling, rearing and/or grooming behaviors. The behavioral effects of methamphetamine (1.0 mg/kg s.c.) were almost completely antagonized by pretreatment with the dopamine D2 receptor antagonist, S(-)-sulpiride (3.0 and/or 10.0 mg/kg i.p.), but not with the dopamine D1 receptor antagonist, SCH 23390 (0.01 or 0.03 mg/kg i.p.). Although dynorphin A-(1-13) (3.0 or 12.5 micrograms i.c.v.) alone did not produce any significant effects on behavior, the methamphetamine (1.0 mg/kg s.c.)-induced increase in circling ipsilateral to the injection side was markedly enhanced by dynorphin A-(1-13) (12.5 micrograms i.c.v.). In contrast, the peptide (12.5 micrograms i.c.v.) inhibited the methamphetamine (1.0 mg/kg s.c.)-induced increase in rearing, whilst the increase in grooming remained unchanged. The effects of dynorphin A-(1-13) (12.5 micrograms i.c.v.) were fully reversed by the opioid antagonist, Mr 2266 (5.6 mg/kg s.c.). These results suggest that the unilateral administration (i.c.v.) of dynorphin A-(1-13) inhibits the activity of dopamine-elicited neurotransmission, resulting in an increase in ipsilateral circling and in a decrease in rearing.

Effects of [D-Ala2, D-Leu5]enkephalin and [D-Pen2, L-Pen5]enkephalin on apomorphine-induced motor activity in the mouse.

The effects of intracerebroventricular injections of opioid peptides such as DADL [( D-Ala2, D-Leu5]enkephalin) and DPLPE [( D-Pen2, L-Pen5]enkephalin) with different degrees of selectivity for delta- over mu-receptor on apomorphine (0.1, 0.3, 1.0 and/or 3.0 mg/kg)-induced motor activity were investigated in the mouse using multi-dimensional behavioral analyses. Lower doses (0.1 and 0.3 mg/kg) of apomorphine failed to affect significantly motor activity, whilst higher doses (1.0 and 3.0 mg/kg) of the drug produced a marked increase in linear locomotion, circling, rearing, and/or grooming behaviors. DADL (0.03, 0.1 or 0.3 microgram) by itself did not influence behaviors, while the peptide (0.1 and 0.3 microgram) produced a marked inhibition on apomorphine (1.0 but not 3.0 mg/kg)-induced increase in rearing behaviors. Furthermore, the inhibitory effect of DADL (0.3 micrograms) on the apomorphine (1.0 mg/kg)-induced increase in rearing was reversed by treatment with the alkylating agent beta-FNA (beta-funaltrexamine) (5.0 micrograms). In contrast to the effects of DADL, the much more delta-selective opioid agonist DPLPE (0.3, 1.0 or 1.75 micrograms) had no marked effects on apomorphine (1.0 mg/kg)-induced behaviors. These results suggest that delta opioid receptors do not play a principal role in the apomorphine-induced increase in circling, rearing or grooming behaviors.

Receptor-selective opioid peptides fail to affect behavioral responses induced by a low dose of apomorphine in the mouse

The effects of intracerebroventricular injections of the mu-selective opioid agonist DAMGO ([D-Ala2,NMePhe4,Gly-ol]enkephalin), the kappa-selective opioid agonist dynorphin A-(1-13), and the delta-selective opioid agonist DPLPE ([D-Pen2,L-Pen5]enkephalin) on the decrease in different behavioral responses induced by a low dose of apomorphine (0.03 mg/kg) were investigated in the mouse. A low dose (0.03 mg/kg) of apomorphine produced a marked decrease in behavioral responses such as circling and rearing. Although the dopamine D1 antagonist SCH 23390 (0.01 and 0.03 mg/kg) did not influence behavior induced by apomorphine (0.03 mg/kg), the dopamine D2 antagonist sulpiride (3.0 mg/kg) reversed the decrease in circling and rearing behavior induced by apomorphine, suggesting that the effects of apomorphine on circling and rearing are mediated through dopamine D2 autoreceptors. DAMGO (0.003 or 0.01 microgram), dynorphin A-(1-13) (3.0 or 10.0 micrograms), or DPLPE (0.3 and 1.0 microgram) had no significant effects on the apomorphine-induced decrease in circling and rearing behavior. These in vivo results suggest that opioid peptides selective for receptor types fail to influence drug effects mediated by dopamine D2 autoreceptors.

Involvement of hyperglycemia in deposition of aggregated protein in glomeruli of diabetic mice

The aim of this study was to clarify the influence of hyperglycemia on the deposition of aggregated protein in the glomeruli of diabetic mice. KK-A(y) mice injected with aggregated bovine serum albumin accumulated more of it in the glomeruli than did ICR mice. There were no histological alterations in the glomeruli of KK-A(y) mice. KK-A(y) mice given voglibose in mouse-chow for 2 weeks had significantly reduced blood glucose, glycated albumin, and hemoglobin A(1C) levels compared with control mice. The voglibose-treated KK-A(y) mice were injected with aggregated bovine serum albumin and accumulated significantly less albumin in the glomeruli than did the control mice. Pioglitazone decreased blood glucose levels compared with the control, and reduced the glomerular deposition of aggregated albumin. Glomerular aggregated bovine serum albumin levels and blood glucose levels were reduced significantly by the injection of insulin. Six times more advanced glycation endproducts were produced from aggregated bovine albumin than from non-aggregated bovine albumin on incubation with glucose and L-lysine in vitro. Glucose-loaded ICR mice generated more advanced glycation endproducts from aggregated albumin, and had more aggregated bovine albumin in the glomeruli. It was suggested that hyperglycemia contributes to an increase in the deposition of aggregated protein in glomeruli even early on in diabetes.