An antimicrotubule agent, TZT-1027, does not induce neuropathologic alterations which are detected after administration of vincristine or paclitaxel in animal models.

One of the major dose-limiting toxicities induced by antimicrotubule antitumor agents such as vinca alkaloids and taxanes is peripheral neuropathy. The neurotoxicity of TZT-1027 (a dolastatin 10 derivative antimicrotubule agent) was thus assessed using the animal models for antimicrotubule agent-induced neurotoxicity. Rabbits were intravenously given TZT-1027 or vincristine weekly for 5 weeks. In the mouse study, TZT-1027, vincristine or paclitaxel was intravenously given every 2 days and/or weekly. Despite the neuropathologic evidence such as myelinated axonal and fiber degeneration in the peripheral nerves and in the sensory tracts of the spinal cord following the treatment with vincristine or paclitaxel, no drug-induced alteration was observed in the TZT-1027 groups. Although there are reports that some other dolastatin derivatives with antimicrotubule activity showed no neurotoxic potential in humans, the present study represents the first demonstration in experimental animals that a dolastatin derivative has no, or at least a lower, neurotoxic potential compared to other antimicrotubule agents.

Opioid receptor agonists selective for mu and kappa receptors attenuate methamphetamine-induced behavioral sensitization in the mouse.

The effects of intracerebroventricular (i.c.v.) injection of the mu-selective opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) and the kappa-selective opioid receptor agonist dynorphin A-(1-13) on the development of methamphetamine-induced behavioral sensitization in the mouse were determined using multidimensional behavioral analyses based upon a capacitance system. Methamphetamine (2 mg/kg, s.c.) was administered to mice on 6 occasions at 3- or 4-d intervals. The methamphetamine-induced increase in linear locomotion and circling was markedly augmented by repeated administrations (3 or more times) of the drug, showing behavioral sensitization. Although repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior, repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) attenuated the behavioral sensitization induced by methamphetamine (2 mg/kg, s.c.). The attenuating effects of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) were fully reversed by withdrawal of these drugs for 3 weeks. Additionally, a single administration of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior; DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) only attenuated the behavioral sensitization which had previously been developed by methamphetamine (2 mg/kg,s.c.). These results suggest that opioid receptor agonists selective for mu and kappa receptors play an inhibitory role in the development of methamphetamine-induced behavioral sensitization.

Intrastriatal injection of opioid receptor agonists inhibits apomorphine-induced behavior in 6-hydroxydopamine-treated mice.

The effects of intrastriatal (i.st.) injections of mu-, delta-, and kappa-selective opioid receptor agonists on the augmentation of apomorphine-induced behaviors were determined in 6-hydroxydopamine-treated mice by using multidimensional behavioral analyses. 6-Hydroxydopamine (16 mu g/mu l, i.st.) was unilaterally injected into the striatum 30 min after pretreatment with desipramine (25 mg/kg, s.c). Mice were tested 14 days after injection of 6-hydroxydopamine. Apomorphine (0.5 mg/kg, s.c.) produced a marked increase in linear locomotion, contralateral circling and/or rearing behavior in 6-hydroxydopamine- but not vehicle-treated mice. Although the mu-selective opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) (0.1 and 0.3 ng, i.st.) or the kappa-selective opioid agonist dynorphin A-(1-13) (0.1 and 0.3 mu g, i.st.) did not produce any significant effects on behavior, these peptides had an inhibitory effect on the apomorphine (0.5 mg/kg, s.c.)-induced increase in behavioral responses such as linear locomotion, contralateral circling and/or rearing behavior in 6-hydroxydopamine-treated mice. The inhibitory effects of DAMGO (0.3 ng, i.st.) and dynorphin A-(1-13) (0.3 mu g, i.st.) were fully reversed by selective opioid receptor antagonists such as beta-funaltrexamine (5 mu g, i.c.v.) and (--)-(1R,5R,9R)-5,9-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorph an (Mr2266) (10 mg/kg, s.c.), respectively. In contrast, the delta-selective opioid receptor agonist [D-Pen2,L-Pen5]enkephalin (DPLPE) (0.03, 0.1 or 0.3 mu g, i.st.) had no marked effects on the apomorphine (0.5 mg/kg, s.c.)-induced behavior in 6-hydroxydopamine-treated mice. These results suggest that the stimulation of mu- and kappa- but not delta-opioid receptors plays an inhibitory role in the behavioral augmentation induced by the activation of postsynaptic dopamine receptors in the striatum sensitized with 6-hydroxydopamine.

Differential modulation of behavioral responses by [D-Ala2, NMePhe4, Gly-ol]enkephalin, [D-Ala2] deltorphin II and [D-Pen2, L-Pen5]enkephalin in the mouse.

The effects of [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO), a mu-selective opioid receptor agonist, [D-Ala2]deltorphin II (DELT) and [D-Pen2, L-Pen5]enkephalin (DPLPE), delta-selective opioid receptor agonists, on different behavioral responses were investigated in mice by multidimensional behavioral analyses. DAMGO (0.1 and/or 0.3 microgram) produced a marked increase in circling, rearing and grooming within 15-30 min after the start of behavioral measurements. DELT (0.3, 1.0 and/or 3.0 micrograms) produced a significant increase in linear locomotion and circling within 15-30 min after the start of behavioral measurements, whereas DPLPE (10.0 micrograms) increased only circling. The behavioral effects of DAMGO, DELT or DPLPE were almost completely antagonized by beta-funaltrexamine (2.5 and 5.0 micrograms) or naltrindole (3.0 and 10.0 mg/kg). These results suggest that opioid peptides selective for receptor types elicit different behavioral responses in mice. Moreover, the different behavioral effects between DPLPE and DELT may be due to the delta opioid receptor subtypes such as delta-1 and delta-2.

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.

DAMGO ([D-Ala2,NMePhe4,Gly-ol]enkephalin), but not DPLPE ([D-Pen2,L- Pen5]enkephalin), specifically inhibits methamphetamine-induced behavioral responses in the mouse.

The effects of intracerebroventricular (i.c.v.) injections of mu- and delta-selective opioid agonists on the methamphetamine-induced behavioral alterations in the mouse were determined by using multi-dimensional behavioral analyses. Methamphetamine (1.0 mg/kg) produced a marked increase in linear locomotion, circling, rearing and grooming behavior. Although the mu-selective opioid agonist [D-Ala2,NMePhe4,Gly-ol]enkephalin (DAMGO) (0.003 and 0.01 microgram) itself did not significantly affect different behavioral responses, DAMGO (0.003 and/or 0.01 microgram) antagonized the methamphetamine (1.0 mg/kg)-induced increase in behavioral responses such as linear locomotion, circling, rearing and grooming. Additionally, the effects of DAMGO (0.01 microgram) on the methamphetamine (1.0 mg/kg)-induced behavioral responses were fully reversed by pretreatment with the mu-selective alkylating agent beta-funaltrexamine (beta-FNA) (5.0 micrograms). In contrast, the delta-selective opioid agonist [D-Pen2,L-Pen5]enkephalin (DPLPE) (0.3 or 1.0 microgram) had no marked effects on the methamphetamine (1.0 mg/kg)-induced behavioral responses. These results suggest that the stimulation of mu but not delta opioid receptors plays an inhibitory role in the methamphetamine-induced behavioral responses.

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.

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.

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.

Combination of a delta opioid receptor agonist but not a mu 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.

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.

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.

[D-Ala2,NMePhe4,Gly-ol5]enkephalin, but not [D-Pen2,L-Pen5]enkephalin, specifically inhibits behaviors induced by the dopamine D2 agonist RU 24213.

The effects of intracerebroventricular injection (10 microliters) of mu- and delta-selective opioid peptides on behaviors induced by the dopamine D2-selective agonist RU 24213 were investigated in the mouse, using multi-dimensional behavioral analyses. Fifteen to 30 min after the start of behavioral measurements, a 3.0 mg/kg dose of RU 24213 produced a marked increase in linear locomotion, circling, rearing and grooming behaviors. Although the mu-selective opioid peptide [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO) (0.003 and 0.01 microgram) itself did not significantly affect behaviors, DAGO (0.01 microgram) antagonized the RU 24213 (3.0 mg/kg)-induced increase in behaviors such as linear locomotion, circling, rearing, and grooming. Additionally, the effects of DAGO on RU 24213-induced behaviors were fully reversed by treatment with the mu-selective alkylating agent beta-funaltrexamine (beta-FNA) (5.0 micrograms). In contrast, the delta-selective opioid peptide [D-Pen2,L-Pen5]enkephalin (0.3 or 1.0 micrograms) had no marked effects on RU 24213 (3.0 mg/kg)-induced behaviors. These results suggest that mu- but not delta-opioid receptors play an inhibitory role in the behaviors induced by the selective activation of dopamine D2 receptors.

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.