Related Experiment Video
Updated: Feb 18, 2026
Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
Published on: May 10, 2018
The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice
Christina McDonnell1,2, Sergi Leánez3,4, Olga Pol5,6
1Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau, 08025 Barcelona, Spain. christina.mcdonnell@e-campus.uab.cat.
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.
Insights
Activating the Nrf2/HO-1 pathway reduces pain and improves cannabinoid receptor 2 (CB2R) agonist effectiveness in type 2 diabetic mice. This antioxidant approach shows promise for treating diabetic neuropathy.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Diabetic neuropathy is a common complication of type 2 diabetes.
- The Nrf2/HO-1 pathway plays a role in inhibiting neuropathy.
- The impact of Nrf2/HO-1 on cannabinoid receptor 2 (CB2R) antinociception is unknown.
Purpose of the Study:
- To investigate the effect of the Nrf2/HO-1 pathway on type 2 diabetes-associated neuropathy.
- To determine if Nrf2/HO-1 activation potentiates CB2R agonist antinociceptive effects.
- To assess the therapeutic potential for painful diabetic neuropathy.
Main Methods:
- Used type 2 diabetic (db/db) mice treated with cobalt protoporphyrin IX (CoPP) or sulforaphane (SFN).
- Evaluated mechanical allodynia, hyperglycemia, and obesity.
- Assessed antinociceptive effects of CB2R agonists (JWH-015, JWH-133) with/without CoPP or SFN.
- Measured expression of Nrf2, HO-1, NQO1, JNK, and CB2R.
Main Results:
- CoPP treatment reduced allodynia, hyperglycemia, and weight gain in db/db mice.
- CoPP enhanced HO-1/NQO1 levels and reduced JNK phosphorylation.
- Both CoPP and SFN improved the antiallodynic effects of CB2R agonists.
- Nrf2/HO-1 activation increased CB2R expression.
Conclusions:
- The Nrf2/HO-1 pathway activation inhibits neuropathy and metabolic dysfunction in type 2 diabetes.
- Activating the Nrf2/HO-1 pathway potentiates the antinociceptive effects of CB2R agonists.
- This antioxidant pathway is a potential therapeutic strategy for painful diabetic neuropathy.
