[What do you expect for laboratory animal science?].
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Animal Technicians↗
Biomedical subjects
K Kisara
Publications and source records attributed to K Kisara.
Antinociceptive effects in the formalin and capsaicin tests after intrathecal administration of substance P analogues in mice.
The antinociceptive effect of substance P- and substance P-(6-11) analogues containing D-histidine (D-His) in position 9 was examined in mice in the formalin and capsaicin tests. [D-Arg1,D-Trp7,9,Leu11]substance P (spantide) was used as reference drug. Intrathecal injections of the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol resulted in no significant antinociception as measured in the 2.0% formalin test, although spantide was antinociceptive in the early and late phases. The early response induced by 0.0625% formalin was reduced significantly by the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol, which were less potent than spantide. The antinociception induced by spantide and a few analogues of substance P and substance P-(6-11) containing D-His was reversed significantly by pretreatment with 2 mg/kg naloxone, an opioid antagonist. The nociceptive response to capsaicin was inhibited significantly by lower doses (2.0 nmol) of the analogues. The antinociception evoked by the analogues was not reversed by naloxone in the capsaicin test. Co-injection of the [D-His9]substance P and substance P-(6-11) analogues at 2.0 nmol selectively decreased substance P-induced licking, biting and scratching without affecting the behavioural responses to NK2 and NK3 receptor agonists. Spantide non-selectively inhibited the behavioural responses produced by not only substance P, but also neurokinin A, D-septide, neurokinin B and eledoisin. The data show that the capsaicin test may be a better method for evaluating neurokinin antagonists than the formalin test.
Analgesics↗
A selective and extremely potent antagonist of the neurokinin-1 receptor.
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Analgesics↗
Spantide-induced antinociception in the opioid mechanism.
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Analgesics↗
Antinociception induced by CP 96,345, a non-peptide NK-1 receptor antagonist, in the mouse formalin and capsaicin tests.
The non-peptide NK-1 receptor antagonist, CP 96,345, has been evaluated for antinociceptive activity in two chemical pain models in the mouse. CP 96,345, injected intrathecally (i.t.) 5 min prior to 2.0% formalin, produced significant antinociception in both the early and late phases of the formalin-induced paw licking procedure. Antinociception could also be observed during the late phase by treatment with CP 96,345 after formalin. In the capsaicin (CAP) test, i.t. injection of CP 96,345 produced a dose-dependent reduction of the paw-licking response at doses much less than antinociceptive doses in the formalin test. Naloxone did not affect antinociception in either test. CP 96,345 evoked a reversible deficit in motor performance as assayed by the rotarod test. The results indicate that i.t. CP 96,345 is antinociceptive in the capsaicin test at doses showing no overt behavioural effects but there is an overlap in doses producing antinociceptive and motor effects in the formalin test.
Analgesics↗
A possible mechanism of antidepressant activity of beta-amyrin palmitate isolated from Lobelia inflata leaves in the forced swimming test.
A mechanism of antidepressant activity of beta-amyrin palmitate was studied using the forced swimming method in mice. Beta-amyrin palmitate (10 mg/kg) reduced the increase in the duration of immobility induced by tetrabenazine (100 and 200 mg/kg), but showed no effect on that in mice treated with alpha-methyl-para-tyrosine (500 mg/kg). Beta-amyrin palmitate (5 and 10 mg/kg) decreased the duration of immobility in mice treated with desipramine plus 6-hydroxy-dopamine (50 micrograms/mouse), but did not affect that induced by nomifensine plus 6-hydroxydopamine. The decreased immobility produced by desipramine (15 mg/kg) was not affected by beta-amyrin palmitate. A study of norepinephrine release in mouse brain synaptosomes indicated that beta-amyrin palmitate caused a release of [3H]norepinephrine. The results of the present study suggest that beta-amyrin palmitate might release norepinephrine from newly synthesized pools, and thus, it might activate noradrenergic activity.
Animals↗
Tolerance and cross-tolerance to the antinociceptive effects of [D-Arg2]-dermorphin tetrapeptide analogue and morphine.
Rats were given repeated subcutaneous injections of [D-Arg2, Sar4]-dermorphin (1-4) [DAS-DER-(1-4)] and/or morphine over a period of 4 or 7 days. Antinociception was determined at 90 min for DAS-DER (1-4) and 30 min for morphine after each morning injection (9:00 a.m.), using the tail-flick and digit pinching tests in rats. Subcutaneous administration of DAS-DER (1-4) and morphine produced the development of antinociceptive tolerance, respectively. A marked tolerance to DAS-DER (1-4) and morphine was seen in rats made tolerant to morphine. However, administration of morphine produced no significant decrement in the antinociceptive activity in rats made tolerant to DAS-DER (1-4). These results suggest that the site of action of DAS-DER (1-4) may be more limited than that of morphine in the nociceptive pathways, for lack of its antinociceptive efficacy in morphine-tolerant rats.
Amino Acid Sequence↗
Possible involvement of the spinal substance P system in pilocarpine-induced scratching in mice.
IT administration of pilocarpine in the spinal subarachnoid space of mice produced a dose-related hindlimb scratching. When coadministered with substance P IT, the pilocarpine-induced scratches were enhanced by high doses of substance P but not by subthreshold doses. This characteristic behavioral response was inhibited dose dependently by IT coadministration of spantide [D-Arg1, D-Trp7,9,Leu11] substance P. Significant antagonistic effects of [D-Phe7,D-His9] substance P (6-11), a selective antagonist for substance P receptors, and substance P (1-7), a substance P N-terminal fragment, were observed against the pilocarpine-induced scratching. Pretreatment with substance P antiserum resulted in the reduction of the response to pilocarpine. When coadministered IT with pilocarpine, atropine potently inhibited pilocarpine-induced scratching. These results demonstrate that not only muscarinic receptors but also substance P-containing neurons in the mouse spinal cord may be involved in elicitation of the scratching behavior following IT injection of pilocarpine.
Afferent Pathways↗
Theophylline-induced nociceptive behavioral response in mice: possible indirect interaction with spinal N-methyl-D-aspartate receptors.
Intrathecal administration of an adenosine receptor antagonist, theophylline, elicited nociceptive behavior such as licking, biting and scratching in mice. This behavioral response was dose-dependently reduced by simultaneous injection of an adenosine receptor agonist, 5'-N6-ethylcarboxamidoadenosine, or a selective N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate. This theophylline-induced behavior was not significantly reduced by the substance P (SP) analogue, the neurokinin receptor antagonist, [D-Arg1, D-Trp7.9, Leu11]SP (spantide). These results suggest the possibility that theophylline-induced nociceptive behavior may be mediated through interactions with both spinal adenosine- and NMDA receptors separately, or only through interaction(s) with adenosine receptors localized on the axon terminals of excitatory amino acid neurons. Present data have failed to reveal involvement of SP.
2-Amino-5-phosphonovalerate↗
Pharmacological properties of beta-amyrin palmitate, a novel centrally acting compound, isolated from Lobelia inflata leaves.
Effects of beta-amyrin palmitate isolated from the leaves of Lobelia inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, beta-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg-1). beta-Amyrin palmitate (5, 10 and 20 mg kg-1) or mianserin (5, 10 and 20 mg kg-1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg-1) increased locomotor activity and potentiated methamphetamine-induced hyperactivity. beta-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg-1) and imipramine (10 and 20 mg kg-1) antagonized the reserpine-induced effect. Unlike imipramine, beta-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. beta-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg-1) decreased it in a dose-dependent manner. A potentiating effect of beta-amyrin palmitate (5, 10 and 20 mg kg-1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg-1) but weaker than that of mianserin (2.5, 5 and 10 mg kg-1). These results suggest that beta-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
An alpha-adrenoceptor-mediated mechanism of hypoactivity induced by beta-amyrin palmitate.
Inhibitory effects of beta-amyrin palmitate in locomotor activity of mice were studied by combining this compound with alpha-adrenergic agonists or antagonists and a dopaminergic agonist. beta-Amyrin palmitate (2.5, 5.0 and 10.0 mg kg-1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0.025 mg kg-1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 micrograms, i.c.v.). The inhibitory action of beta-amyrin palmitate was not affected by yohimbine (1.5 mg kg-1, i.p.), but was potentiated by prazosin (0.75 mg kg-1, i.p.). When combined with a dopaminergic agonist, apomorphine (2.0 mg kg-1, i.p.), beta-amyrin palmitate (5.0 and 10.0 mg kg-1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that beta-amyrin palmitate might inhibit alpha 1-adrenoceptors.
Adrenergic alpha-Agonists↗
[Central effects of iohexol and iopamidol, non-ionic contrast media].
Central effects of intravenously (i.v.)-administered iohexol were compared with those of iopamidol in a series of tests. Mannitol was used as a reference. As assayed by the primary screening test based on Irwin's method, i.v. administration of mannitol resulted in a score of 0 in ddY mice and a score of 0.6 in ICR mice in the startle response. These results were not different from the data of both iohexol and iopamidol. Iopamidol at a dose of 1750 mgI/kg produced an inhibitory effect on the spontaneous locomotor activity. Iohexol at a dose of 7000 mgI/kg potentiated the duration of thiopental-induced narcosis. Hypothermia was caused by high doses of both iohexol and iopamidol. Electric stimulus increased the mortality of mice pretreated with high doses of iohexol and iopamidol. Both drugs had no notable activities in the anticonvulsant, electroencephalic, muscle relaxant and antinociceptive tests. These results indicate that both iohexol and iopamidol do not necessarily possess a similar pharmacological action. Judging from the LD50 of approximately 15000 mgI/kg for both drugs, they seem unlikely to have a specific pharmacological action on the central nervous system.
Animals↗
A selective and extremely potent antagonist of the neurokinin-1 receptor.
Sendide [Tyr6,D-Phe7,D-His9]-substance P(6-11) has been examined by measurements of ligand binding to crude membrane fractions and by functional tests on the spinally mediated behavioral response. Sendide potently displaced [3H]-labeled substance P (SP) binding to mouse spinal cord membranes in a competitive manner. In vivo, sendide, intrathecally co-injected with SP, competitively antagonized SP-induced scratching, biting and licking. The behaviors elicited by physalaemin, septide and [Sar9, Met(O2)11]-SP were also reduced by co-administration of sendide. Large doses of sendide were needed to reduce the action of neurokinin A, D-septide, neurokinin B and eledoisin. The in vitro and in vivo pharmacological profile of sendide demonstrated that it is a selective and extremely potent antagonist of the neurokinin-1 receptor.
Amino Acid Sequence↗
Comparison of opioid properties between D-Arg-containing dipeptides and tetrapeptides.
Since the D-Arg-containing dipeptides, H-Tyr-D-Arg-OMe (TDA) and H-Tyr(Et)-D-Arg-OMe, and D-Arg2-substituted dermorphin N-terminal tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-OEt (TDAPG) and H-Tyr(Et)-D-Arg-Phe-Gly-OEt gave different pharmacological responses in vivo, opioid interaction and structure-activity relationships have been investigated in vitro. In the isolated guinea-pig ileum assay, the tetrapeptides were potently inhibitory, their activity markedly exceeding that of the dipeptides. In particular, the first tetrapeptide had twice the activity of morphine, while the potency of the dipeptides was less than one twentieth that of morphine. Also in the opioid receptor binding assay, tetrapeptides had a higher affinity than the dipeptides. IC50 values of tetrapeptides were 8.46 and 23.7 nM, respectively, which were lower than that of morphine. Ethylation of the Tyr residue of TDA much increased the opioid activity whereas that of TDAPG greatly decreased it. All peptides used were extremely stable to aminopeptidase-M and carboxypeptidase-Y and had an inhibitory effect on enkephalin (EK)-degrading enzymes. From these results, it appears that the effects of the tetrapeptides are due mainly to specific interaction with opioid receptors, whereas the dipeptides do not act specifically on the opioid receptors, but are involved in non-opioid mechanisms. The resistance to enzymes and inhibitory effect of the peptides used on the EK-degrading enzymes may also account for their potent and long-lasting opioid-like activities.
Amino Acid Sequence↗
Different effects of peptidase inhibitors on dermorphin- and on [D-Arg2]dermorphin-induced antinociceptive activity.
The antinociceptive effects produced by the intracerebroventricular (i.c.v.) injection of dermorphin and [D-Arg2]dermorphin were compared in conscious mice, using the combined administration of peptidase inhibitors. Nociception was assessed using a tail pressure assay. Dermorphin-induced antinociception was not potentiated by simultaneous administration of amastatin or captopril as judged from the ED50 values. Co-administration of dermorphin and amastatin gave a longer duration than with dermorphin alone, whereas there was no significant effect on duration with captopril. The antinociceptive activity of dermorphin was significantly enhanced when the heptapeptide was injected simultaneously with both peptidase inhibitors. This result indicates that the heptapeptide sequence is required for the full expression of intrinsic opioid activity of dermorphin. In contrast, co-administration of amastatin brought about a significant enhancement of the antinociceptive activity induced by i.c.v. administration of [D-Arg2]dermorphin, whereas the effect of [D-Arg2]dermorphin was markedly decreased by the concurrent administration of captopril or thiorphan. The potency of captopril was much greater than that of thiorphan. The present results suggest that [D-Arg2]dermorphin may be transformed metabolically to a peptide which has potent antinociceptive activity.
Analgesics, Opioid↗
Naloxone-reversible effect of spantide on the spinally mediated behavioural response induced by neurokinin-2 and -3 receptor agonists.
[D-Arg1, D-Trp7,9, Leu11]-substance P (spantide) was tested for antagonism against the licking, biting and scratching response induced by various neurokinin (NK) receptor agonists and bombesin (Bom) in mice. When co-administered with substance P (SP) intrathecally, spantide reduced the SP-induced behavioural responses in a dose-dependent manner. The duration of this antagonistic effect was approximately 30 min. Behavioural responses induced by physalaemin (Phy), [pGlu6, L-Pro9]-SP (6-11) (septide), [pGlu6, D-Pro7]-SP (6-11) (D-septide) and eledoisin (Ele) were also dose-dependently decreased by relatively small doses of spantide. Higher doses of spantide were needed to reduce the behavioural responses induced by [Sar9, Met (O2)11]-SP, neurokinin A (NK A) and neurokinin B (NK B). No significant effect of spantide was observed against the behavioural responses elicited by Bom. Pretreatment with naloxone, an opioid antagonist, resulted in a reversible effect on the behavioural reduction of NK-2 and NK-3 receptor agonists produced by spantide. However, the effect of spantide on the NK-1 receptor agonist-induced response was unchanged by naloxone. In homogenates of mouse spinal cord, competition studies confirmed that the binding of the opioid ligand [3H]naloxone was displaced by spantide with a low but measurable affinity. These results suggest that the behavioural response to NK-2 and NK-3 receptor agonists may be partially inhibited by spantide through the activation of opioid system in the mouse spinal cord.
Analgesics↗
Chronic clonidine treatment and its termination: effects on penile erection and ejaculation in the dog.
The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 micrograms/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p.). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.
Adrenergic alpha-Antagonists↗
The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord.
A capsaicin test involving peripheral nociception, which produces behaviour similar to that elicited by formalin, is described in mice. Capsaicin was injected subcutaneously (s.c.) into the dorsal surface of a hindpaw and the time the animals spent licking the paw was recorded. Doses of capsaicin of 6.25-1600 ng induced nociception, during a period of 5 min, starting immediately after injection and disappearing completely at 10 min. Intrathecally (i.t.) administered [D-Arg1,D-Trp7,9,Leu11]substance P (spantide), a tachykinin antagonist and [D-Phe7,D-His9]substance P (6-11), a selective antagonist of substance P (SP), inhibited the capsaicin-induced behaviour, in a dose-dependent manner. This licking behaviour was also inhibited by intrathecal administration of SP antiserum but not by somatostatin (SOM) antiserum. Intrathecal pretreatment with capsaicin resulted in a marked reduction of the licking response, following subcutaneous injection of capsaicin into the paw. Capsaicin-induced licking was not affected by intrathecal administration of cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-(OBz)-Thr], a SOM antagonist and by intrathecal pretreatment with cysteamine, a SOM depletor. This nociceptive test may allow discrimination between SP- and SOM-mediated responses in the spinal cord of the mouse.
Analgesics↗