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The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice

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Abstract

Rationale

The activation of cannabinoid 2 receptors (CB2R) attenuates chronic pain, but the role played by carbon monoxide synthesized by the inducible heme oxygenase 1 (HO-1) on the anti-nociceptive effects produced by a selective CB2R agonist, JWH-015, during painful diabetic neuropathy remains unknown.

Objectives and methods

In streptozotocin (STZ)-induced diabetic mice, the anti-allodynic and anti-hyperalgesic effects of the subcutaneous administration of JWH-015 alone or combined with the intraperitoneal administration of a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer (CORM-2)) or an HO-1 inducer compound (cobalt protoporphyrin IX (CoPP)) at 10 mg/kg were evaluated. Reversion of JWH-015 anti-nociceptive effects by the administration of an HO-1 inhibitor (tin protoporphyrin IX (SnPP)) and a CB2R antagonist (AM630) was also evaluated. Furthermore, the protein levels of HO-1, neuronal nitric oxide synthase (NOS1), and CB2R in diabetic mice treated with CORM-2 and CoPP alone or combined with JWH-015 were also assessed.

Results

The administration of JWH-015 dose dependently inhibited hypersensitivity induced by diabetes. The effects of JWH-015 were enhanced by their coadministration with CORM-2 or CoPP and reversed by SnPP or AM630. The increased protein levels of HO-1 induced by CORM-2 and CoPP treatments were further enhanced in JWH-015-treated mice. All treatments similarly enhanced the peripheral expression of CB2R and avoided the spinal cord over-expression of NOS1 induced by diabetes.

Conclusions

The activation of HO-1 enhanced the anti-nociceptive effects of JWH-015 in diabetic mice, suggesting that coadministration of JWH-015 with CORM-2 or CoPP might be an interesting approach for the treatment of painful diabetic neuropathy in mice.

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Acknowledgments

This work was supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea (Grants PS0900968 and PI1400927).

The experiments performed in this study comply with the current laws of Spain.

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    Authors and Affiliations

    1. Grup de Neurofarmacologia Molecular, Institut d’Investigació Biomèdica Sant Pau and Institut de Neurociències. Facultat de Medicina, Edifici M2-115, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain

      Sílvia Castany, Mireia Carcolé, Sergi Leánez & Olga Pol

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    1. Sílvia Castany
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    2. Mireia Carcolé
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    3. Sergi Leánez
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    4. Olga Pol
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    Correspondence to Olga Pol.

    Ethics declarations

    All experiments were conducted between 9:00 AM and 5:00 PM and carried out according to the animal guidelines of the European Communities Council (86/609/ECC, 90/679/ECC, 98/81/CEE, 2003/65/EC, and Commission Recommendation 2007/526/EC) and approved by the local Ethical Committee of our Institution (Comissió d’Etica en l’Experimentació Animal i Humana de la Universitat Autònoma de Barcelona). All efforts were made to minimize animal suffering and to reduce the number of animals used.

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    Sílvia Castany and Mireia Carcolé contributed equally to this work.

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    Castany, S., Carcolé, M., Leánez, S. et al. The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice. Psychopharmacology 233, 2209–2219 (2016). https://doi.org/10.1007/s00213-016-4271-4

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    • DOI: https://doi.org/10.1007/s00213-016-4271-4

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