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The Use of the Selective Imidazoline I1 Receptor Agonist Carbophenyline as a Strategy for Neuropathic Pain Relief: Preclinical Evaluation in a Mouse Model of Oxaliplatin-Induced Neurotoxicity
- Source :
- Neurotherapeutics
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Anti-cancer therapy based on the repeated administration of oxaliplatin is limited by the development of a disabling neuropathic syndrome with detrimental effects on the patient’s quality of life. The lack of effective pharmacological approaches calls for the identification of innovative therapeutic strategies based on new targets. We focused our attention on the imidazoline I(1) receptor (I(1)-R) and in particular on the selective I(1)-R agonist 2-(1-([1,1′-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline). The purpose of this work was the preclinical evaluation of the efficacy of carbophenyline on oxaliplatin-induced neuropathic pain in mice. Carbophenyline, acutely per os administered (0.1–10 mg kg(−1)), induced a dose-dependent anti-hyperalgesic effect that was completely blocked by the pre-treatment with the I(1)-R antagonist 3 or the I(1)/α(2) receptor antagonist efaroxan, confirming the I(1)-R-dependent mechanism. Conversely, pre-treatment with the I(2)-R antagonist BU224 did not block the anti-nociceptive effect evoked by carbophenyline. Repeated oral administrations of carbophenyline (1 mg kg(−1)) for 14 days, starting from the first day of oxaliplatin injection, counteracted the development of neuropathic pain in all behavioral tests (cold plate, Von Frey, and paw pressure tests) carried out 24 h after the last carbophenyline treatment on days 7 and 14. In the dorsal horn of the spinal cord, carbophenyline significantly decreased the oxaliplatin-induced astrocyte activation detected by immunofluorescence staining by the specific labelling with GFAP antibody. In conclusion, carbophenyline showed anti-neuropathic properties both after acute and chronic treatment with preventive effect against oxaliplatin-induced astrocyte activation in the spinal cord. Therefore, I(1)-R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00873-y) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Agonist
medicine.drug_class
Drug Evaluation, Preclinical
Imidazoline receptor
Antineoplastic Agents
Pharmacology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Animals
Humans
Pharmacology (medical)
Pain Measurement
Dose-Response Relationship, Drug
business.industry
Imidazoles
Neurotoxicity
Antagonist
Efaroxan
medicine.disease
Oxaliplatin
030104 developmental biology
medicine.anatomical_structure
chemistry
Neuropathic pain
Neuralgia
Original Article
Imidazoline Receptors
Neurology (clinical)
business
HT29 Cells
030217 neurology & neurosurgery
medicine.drug
Astrocyte
Subjects
Details
- ISSN :
- 18787479 and 19337213
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Neurotherapeutics
- Accession number :
- edsair.doi.dedup.....796952011986169963f717a4bf9f10d4