Analgesic Effect of a Mixed T-Type Channel Inhibitor/CB2 Receptor Agonist
Open accessAbstract
Background: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. Results: NMP-181 action on CB 1 and CB 2 receptors was characterized in radioligand binding and in vitro GTPγ[35 S] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Cav3.2 currents with IC 50 values in the low micromolar range and acted as a CB 2 agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in Ca v 3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB 2 antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB 1 antagonist). Conclusions: Our work shows that both T-type channels as well as CB 2 receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T-type/cannabinoid receptor ligands.
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Systemic or intrathecal administration of NMP-181 attenuates CFA-induced mechanical hyperalgesia.
“Systemic or intrathecal administration of NMP-181, which acts as a CB 2 receptor agonist and T-type channel inhibitor, also attenuates CFA-induced mechanical hyperalgesia (Gadotti et al, 2013).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Gadotti et al, 2013
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Self-citationVoltage-Gated Ca2+ Channels. Lessons from Knockout and Knock-in Mice
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Self-citationVoltage-Gated Ion Channels as Molecular Targets for Pain
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Self-citationDeveloping T-type calcium channel blockers as potential therapies for pain.
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Protein Kinase A and Epac Mediate Chronic Pain after Injury
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Antihyperalgesic effect of joint mobilization requires Cav3.2 calcium channels
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Self-citationT-Type Calcium Channels in Pain Neuronal Circuits
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Self-citationAdditional file 1 of Antihyperalgesic effect of joint mobilization requires Cav3.2 calcium channels
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Self-citation
- Authors
- Gadotti, V. M., You, H., Petrov, R. R., Berger, N. D., Diaz, P., & Zamponi, G. W.
- Affiliations
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
- University of Calgary (CA)
- University of Montana (US)
- Corresponding author
- Zamponi, Gerald W
- Venue
- Molecular Pain
- Publisher
- SAGE Publications
- Published
- 2013-01-01
- Volume
- 9
- Pages
- 32-32
- ISSN
- 1744-8069 (ISSN-L)
- PMC
- PMC3703287
- OpenAlex
- W2167180948
- Cited by
- 45
- References
- 61
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 1
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Pain (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Libraries and Cultural Resources (University of Calgary) (submittedVersion, cc-by)
- Funders
- Alberta Innovates
- National Institutes of Health (5p30ns055022-05, HHSN-271-2008-00025-C)
- U.S. Public Health Service (HHSN-271-2008-00025-C)
- University of North Carolina at Chapel Hill
- Canadian Institutes of Health Research
- National Institute of Mental Health (HHSN271200800025C)
- National Institute of Neurological Disorders and Stroke (P30-NS055022)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- CB2 receptor agonist, Cav3.2, cannabinoid receptors, antinociception, chronic pain, formalin test, complete Freund's adjuvant, intrathecal administration
- MeSH terms
- Analgesics, Animals, Carbazoles, Cricetulus, Humans, Male, Morpholines, Pain Measurement, Pyrazoles, CHO Cells, Mice, Knockout, Calcium Channels, T-Type, Receptor, Cannabinoid, CB2, Mice, HEK293 Cells
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