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BioAssay: AID 652108

Late-stage results from the probe development effort to identify antagonists of OPRK1: In vivo tail flick assay

Name: Late-stage results from the probe development effort to identify antagonists of OPRK1: In vivo tail flick assay. ..more
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Unspecified(1)
 
 
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AID: 652108
Data Source: The Scripps Research Institute Molecular Screening Center (TAIL_FLICK_SECONDS_IN VIVO)
BioAssay Type: Panel
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-03-15
Hold-until Date: 2013-10-21
Modify Date: 2013-10-21

Data Table ( Complete ):           View All Data
Tested Compound:
Related Experiments
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AIDNameTypeComment
652031Maybridge screen to identify antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based assayScreeningdepositor-specified cross reference: Maybridge screen (OPRK1 inhibitors in singlicate)
652032Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response assayConfirmatorydepositor-specified cross reference: Late-stage dose response (OPRK1 antagonists in quadruplicate)
652033Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response OPRD1 counterscreenConfirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRD1 antagonists in quadruplicate)
652034Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response OPRM1 counterscreenConfirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRM1 antagonists in quadruplicate)
652045Summary of the probe development efforts to identify antagonists of the kappa 1 (OPRK1) opioid receptorSummarydepositor-specified cross reference: Summary (OPRK1 inhibitors)
652075Late-stage results from the probe development effort to identify antagonists of OPRK1: radiometric-based biochemical hERG counterscreen assayOtherdepositor-specified cross reference: Late-stage counterscreen (hERG activity in duplicate)
652076Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based biochemical cytochrome P450 inhibition assayOtherdepositor-specified cross reference: Late-stage assay (cytochrome P450 inhibition)
652077Late-stage fluorescence-based cell-based dose response assay for antagonists of kappa opioid receptor 1 (OPRK1)Confirmatorydepositor-specified cross reference: Late-stage dose response (OPRK1 antagonists in triplicate)
652078Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based pharmacokinetic plasma protein binding assayOtherdepositor-specified cross reference: Late-stage assay (plasma protein binding)
652079Late-stage counterscreen for antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based dose response assay to identify antagonists of Sphingosine 1-Phosphate Receptor 1 (S1P1)Confirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (S1P1 antagonists in triplicate)
652080Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response OPRD1 counterscreen, Set 2Confirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRD1 antagonists in triplicate)
652081Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response OPRM1 counterscreen, Set 2Confirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (OPRM1 antagonists in triplicate)
652082Fluorescence-based cell-based confirmation assay for antagonists of kappa opioid receptor 1 (OPRK1)Otherdepositor-specified cross reference: Confirmation assay (OPRK1 antagonists in triplicate)
652083Late-stage results from the probe development effort to identify antagonists of OPRK1: CEREP radiometric-based biochemical counterscreen panel assayOtherdepositor-specified cross reference: Late-stage counterscreen (CEREP panel)
652084Late-stage results from the probe development effort to identify antagonists of OPRK1: fluorescence-based cell-based dose response assay, Set 2.Confirmatorydepositor-specified cross reference: Late-stage dose response (OPRK1 antagonists 8 replicates)
652085Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based in vivo plasma and brain levelsOtherdepositor-specified cross reference: Late-stage assay (in vivo plasma and brain levels)
652086Late-stage results from the probe development effort to identify antagonists of OPRK1: luminescence-based cell-based dose response counterscreen assay to determine cytotoxicity of test compoundsConfirmatorydepositor-specified cross reference: Late-stage dose response counterscreen (cytotoxicity in quadruplicate)
652087Counterscreen for antagonists of kappa opioid receptor 1 (OPRK1): fluorescence-based cell-based assay to identify antagonists of Sphingosine 1-Phosphate Receptor 1 (S1P1)Otherdepositor-specified cross reference: Counterscreen (S1P1 antagonists in triplicate)
652088Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based biochemical hepatic microsome stability assayOtherdepositor-specified cross reference: Late-stage assay (hepatic microsome stability)
652113Late-stage results from the probe development effort to identify antagonists of OPRK1: LCMS-based parallel artificial membrane permeability (PAMPA) assayOthersame project related to Summary assay
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Lakshmi A. Devi, Mount Sinai School of Medicine
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: R03NS053751
Grant Proposal PI: Lakshmi A. Devi, Mount Sinai School of Medicine
External Assay ID: TAIL_FLICK_SECONDS_IN VIVO

Name: Late-stage results from the probe development effort to identify antagonists of OPRK1: In vivo tail flick assay.

Description:

Potent and selective OPRK antagonists will be useful for studying the mechanisms involved in OPRK-mediated analgesia and may have therapeutic value as novel analgesics with an improved side effect profile to currently available drugs. Studies have identified a role for dynorphin and OPRK stimulation in neuropathic pain (1). The dynorphins act as endogenous agonists at the opioid receptors, including OPRK (2), and the increased dynorphin expression in neuropathic pain also leads to a sustained activation of OPRK (1, 3). The mechanisms and neural circuits in OPRK-mediated analgesia are active areas of study; it is hoped those studies will assist in the development of novel analgesics that bypass OPRK-mediated depression (4-5). A role for dynorphin/OPRK in modulating drug addiction has been proposed (for review, see (6-7)). The function of dynorphin/OPRK systems in addiction appears to be diverse, and may modulate drug-seeking behavior depending on factors such as drug history, pattern of intake, and stress (for review, see (6)). The availability of potent and selective OPRK ligands may help unravel these mechanisms, as well as prove to be of therapeutic utility. Evidence from preclinical studies indicates that the dynorphin/OPRK system may be dysregulated in affective psychiatric disorders (for review, see (6, 8)). However, solid evidence from clinical studies is lacking. There is increasing evidence for a potential involvement of dynorphin/OPRK in schizophrenia; OPRK agonists appear to induce symptoms in humans and animals that are present in schizophrenia (8-10). Thus, the availability of new research tools such as potent and selective OPRK antagonists will facilitate understanding the physiological and pathophysiological mechanisms of dynorphin/OPRK systems and their roles in psychiatric disease in humans.

References:

1. Xu, M., et al., Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci, 2004. 24(19): p. 4576-84.
2. Chavkin, C., I.F. James, and A. Goldstein, Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science, 1982. 215(4531): p. 413-5.
3. Xu, M., et al., Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase. J Neurosci, 2007. 27(10): p. 2570-81.
4. Al-Hasani, R. and M.R. Bruchas, Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology, 2011. 115(6): p. 1363-81.
5. Muschamp, J.W., A. Van't Veer, and W.A. Carlezon, Jr., Tracking down the molecular substrates of stress: new roles for p38alpha MAPK and kappa-opioid receptors. Neuron, 2011. 71(3): p. 383-5.
6. Tejeda, H.A., T.S. Shippenberg, and R. Henriksson, The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci, 2012. 69(6): p. 857-96.
7. Yoo, J.H., I. Kitchen, and A. Bailey, The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us? Br J Pharmacol, 2012. 166(7): p. 1993-2014.
8. Schwarzer, C., 30 years of dynorphins--new insights on their functions in neuropsychiatric diseases. Pharmacol Ther, 2009. 123(3): p. 353-70.
9. Bortolato, M. and M.V. Solbrig, The price of seizure control: dynorphins in interictal and postictal psychosis. Psychiatry Res, 2007. 151(1-2): p. 139-43.
10. Sheffler, D.J. and B.L. Roth, Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor. Trends Pharmacol Sci, 2003. 24(3): p. 107-9.

Keywords:

OPRK1, kappa, opioid, receptor, mouse, tail flick, tail flick assay, latency, Nor-BNI, U-69593, antagonist, inhibitor, inhibit, pain, analgesic, neuropathic pain, drug addiction, addiction, Scripps, Mouse Behavioral Assessment Core, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Panel Information
Assays
PID§NameSubstancePanel TargetsDescriptionAdditional Information
ActiveInactive
11 hourTaxonomy id: 10090
224 hoursTaxonomy id: 10090
31 weekTaxonomy id: 10090

§ Panel component ID.
Protocol
Assay Overview:

The purpose of this assay is to assess the effect of a lead OPRK antagonist test compound in the Tail Flick assay in mice. The Tail Flick assay is a pain receptive assay in which a mouse is placed within a restraining tube with its tail protruding. The tail is placed on a level surface, radiant heat is applied to the tail and the latency of the mouse to remove its tail from the heat is recorded. This latency is used as a measure to indicate neurological pathology. In this assay, the mice are administered an OPRK agonist and test compound, and the ability of test compound to block the analgesic effect of the agonist compound is measured.

Protocol Summary:

This assay was performed by the Mouse Behavioral Assessment Core of The Scripps Research Institute. Ten mice each were pre-treated with test compound (administered i.p. at 10 mg/kg), OPRK antagonist NOR-BNI (administered s.c. 10 mg/kg), or vehicle. Mice were subsequently challenged with OPRK agonist U-69593 (administered i.p. at 2 mg/kg) at one hour, 24 hours, and 1 week post pre-treatment. After each agonist challenge, each moue was tested by application of a heat source three times and the latency time of the mouse to remove its tail from the heat was measured and reported in seconds. Values reported are averages.

List of Reagents:

Reagents were provided by the Mouse Behavioral Assessment Core of The Scripps Research Institute.
Comment
This assay was performed by Mouse Behavioral Assessment Core of The Scripps Research Institute with powder samples of synthesized compound.
Categorized Comment - additional comments and annotations
From PubChem:
Assay Test Type: In vivo
Result Definitions
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TIDNameDescriptionPID§Panel TargetsHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Average Latency at 0 min [1 hour]Average period of latency 0 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.1Floatsec
2Average Latency at 15 min [1 hour]Average period of latency 15 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.1Floatsec
3Average Latency at 30 min [1 hour]Average period of latency 30 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.1Floatsec
4Average Latency at 60 min [1 hour]Average period of latency 60 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.1Floatsec
5Average Latency at 0 min [Control, 1 hour]Average period of latency 0 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.1Floatsec
6Average Latency at 15 min [Control, 1 hour]Average period of latency 15 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.1Floatsec
7Average Latency at 30 min [Control, 1 hour]Average period of latency 30 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.1Floatsec
8Average Latency at 60 min [Control, 1 hour]Average period of latency 60 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.1Floatsec
9Average Latency at 0 min [24 hours]Average period of latency 0 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.2Floatsec
10Average Latency at 15 min [24 hours]Average period of latency 15 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.2Floatsec
11Average Latency at 30 min [24 hours]Average period of latency 30 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.2Floatsec
12Average Latency at 60 min [24 hours]Average period of latency 60 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.2Floatsec
13Average Latency at 0 min [Control, 24 hours]Average period of latency 0 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.2Floatsec
14Average Latency at 15 min [Control, 24 hours]Average period of latency 15 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.2Floatsec
15Average Latency at 30 min [Control, 24 hours]Average period of latency 30 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.2Floatsec
16Average Latency at 60 min [Control, 24 hours]Average period of latency 60 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.2Floatsec
17Average Latency at 0 min [1 week]Average period of latency 0 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.3Floatsec
18Average Latency at 15 min [1 week]Average period of latency 15 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.3Floatsec
19Average Latency at 30 min [1 week]Average period of latency 30 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.3Floatsec
20Average Latency at 60 min [1 week]Average period of latency 60 minutes after agonist challenge for mouse pre-treated with test compound to pull tail away from heat source, expressed in seconds.3Floatsec
21Average Latency at 0 min [Control, 1 week]Average period of latency 0 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.3Floatsec
22Average Latency at 15 min [Control, 1 week]Average period of latency 15 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.3Floatsec
23Average Latency at 30 min [Control, 1 week]Average period of latency 30 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.3Floatsec
24Average Latency at 60 min [Control, 1 week]Average period of latency 60 minutes after agonist challenge for mouse pre-treated with vehicle control to pull tail away from heat source, expressed in seconds.3Floatsec
Additional Information
Grant Number: R03NS053751

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