In:
Pain, Ovid Technologies (Wolters Kluwer Health), Vol. 163, No. 7 ( 2022-07), p. 1414-1423
Abstract:
Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic pain models report alterations in cannabinoid and opioid receptor expression levels; receptors whose activation induces analgesia. We examined whether interactions between CB 1 R and opioid receptors could be targeted for the treatment of diabetic neuropathy. For this, we generated antibodies that selectively recognize native CB 1 R-MOR and CB 1 R-DOR heteromers using a subtractive immunization strategy. We assessed the levels of CB 1 R, MOR, DOR, and interacting complexes using a model of streptozotocin-induced diabetic neuropathy and detected increased levels of CB 1 R, MOR, DOR, and CB 1 R-MOR complexes compared with those in controls. An examination of G-protein signaling revealed that activity induced by the MOR, but not the DOR agonist, was potentiated by low nanomolar doses of CB 1 R ligands, including antagonists, suggesting an allosteric modulation of MOR signaling by CB 1 R ligands within CB 1 R-MOR complexes. Because the peptide endocannabinoid, hemopressin, caused a significant potentiation of MOR activity, we examined its effect on mechanical allodynia and found that it blocked allodynia in wild-type mice and mice with diabetic neuropathy lacking DOR (but have CB 1 R-MOR complexes). However, hemopressin does not alter the levels of CB 1 R-MOR complexes in diabetic mice lacking DOR but increases the levels of CB 1 R-DOR complexes in diabetic mice lacking MOR. Together, these results suggest the involvement of CB 1 R-MOR and CB 1 R-DOR complexes in diabetic neuropathy and that hemopressin could be developed as a potential therapeutic for the treatment of this painful condition.
Type of Medium:
Online Resource
ISSN:
0304-3959
,
1872-6623
DOI:
10.1097/j.pain.0000000000002527
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2022
detail.hit.zdb_id:
1494115-6
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