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Int. J. Mol. Sci. 2017, 18(11), 2268; https://doi.org/10.3390/ijms18112268

The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice

1
Grup de Neurofarmacologia Molecular, Institut d’Investigació Biomèdica Sant Pau, 08025 Barcelona, Spain
2
Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Received: 29 September 2017 / Revised: 25 October 2017 / Accepted: 27 October 2017 / Published: 28 October 2017
(This article belongs to the Special Issue Cannabinoid Signaling in Nervous System)
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Abstract

The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes. View Full-Text
Keywords: antinociception; cannabinoid receptors; diabetic neuropathy; heme oxygenase 1; NAD(P)H: quinone oxidoreductase 1; Nrf2 transcription factor antinociception; cannabinoid receptors; diabetic neuropathy; heme oxygenase 1; NAD(P)H: quinone oxidoreductase 1; Nrf2 transcription factor
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McDonnell, C.; Leánez, S.; Pol, O. The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice. Int. J. Mol. Sci. 2017, 18, 2268.

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