2002 Fiscal Year Final Research Report Summary
Development of a new analgesic drug with tachykinin antagonistic and opioid activities in the spinal cord
| Project/Area Number |
12672235
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Daiichi College of Pharmaceutical Sciences |
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Principal Investigator |
SAKURADA Tsukasa Daiichi College of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, professor, 薬学部, 教授 (80124907)
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| Co-Investigator(Kenkyū-buntansha) |
SAKURADA Chikai Daiichi College of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, associate professor, 薬学部, 助教授 (30279244)
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| Project Period (FY) |
2000 – 2002
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| Keywords | substance P / intrathecal injection / pain-related behavior / NK_1 receptor antagonist / opioid action |
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| Research Abstract |
1) Effects of sendide and [D-Arg^2]sendide on pain-related behavior induced by substance P (SP)
Sendide, given simultaneously with SP, reduced the SP-induced behavioral response with an ID_<50> of 0.3 pmol. [D-Arg^2]sendide co-injected with SP produced a dose dependent reduction with an ID_<50> of 115.5 fmol.
2) Duration of antagonistic action of sendide and [D-Arg^2]sendide
The antagonistic action of sendide on SP-induced behavior at doses of 4.0 and 8.0 nmol lasted for 120 and 180 min, respectively. The duration of the antagonistic effect of [D-Arg^2]sendide at doses of 0.5 and 4.0 pmol was 60 and 120 min, respectively.
3) Effects of naloxone pretreatment on the inhibitory action of sendide and [D-Arg^2]sendide
Naloxone (0.5 - 4.0 mg/kg) pretreatment gave no significant antagonism against sendide. The inhibitory action of [D-Arg^2]sendide on SP-induced behavior was antagonized by naloxone (4.0 mg/kg), but not by lower doses of naloxone (1.0 and 2.0 mg/kg).
4) Binding properties of sendide for NK_1 receptors
Sendide displaced the binding of [^3H]-SP to mouse spinal cord membranes. The Ki for unlabeled SP and sendide was 3.3 ± 0.7 and 4.0 ± 1.0 pM, respectively, indicating that sendide was approximately 800 times more potent than SP.
5) Binding properties of sendide for mu and delta opioid receptors
Sendide displaced the binding of [^3H]-DAMGO to mouse spinal cord membranes. On the basis of Ki values sendide was approximately 100 times as weak as unlabeled binding sites. Sendide had a lower affinity for [^3H]-deltorphin binding sites.
These results suggest that sendide and [D-Arg^2]sendide at lower doses may be a relatively selective action at the tachykinin NK_1 receptors in the spinal cord, and at higher doses these antagonists may possess opioid activities in addition to an antagonistic action at NK_1 receptors.
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