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

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 I1 receptor (I1-R) and in particular on the selective I1-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 I1-R antagonist 3 or the I1/α2 receptor antagonist efaroxan, confirming the I1-R-dependent mechanism. Conversely, pre-treatment with the I2-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, I1-R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain.