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 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 oxaliplatininduced 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.

Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy

“…Pain-related behavior (licking of the hind paw) was determined by recording the time (seconds) of the first sign of licking of the hind paw. The cutoff time of the latency of paw lifting or licking was set at 30 s [24,25].…”

Effects of imidazoline agents in a rat conditioned place preference model of addiction

“…Both IDZ and EFR blocked the antidepressant effect induced by AG (Kotagale et al 2020a ). EFR confirmed the involvement of imidazoline receptors in the antidepressant effect of AG in models of acute and subacute depression in mice (Chen et al 2018 ), in carbophenyline analgesia in neuropathic pain caused by oxaliplatin in mice (Micheli et al 2020 ), in maintaining the respiratory drive in newborn rats (Sato et al 2017 ) and in the cardioprotective effect exerted by dexmedetomidine against ischemia/reperfusion injury in the spontaneously hypertensive rats (Yoshikawa et al 2018 ). EFR stimulated insulin secretion in the MIN6 cell line (Lin et al 2017 ), and IDZ reduced hepatic fibrosis in mice (Xuanfei et al 2017 ).…”

Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence

“…In addition to the above, many other drugs have been identified to reduce oxaliplatin-induced peripheral neuropathy via several therapeutic targets, such as acetylcholine receptors [ 95 , 96 , 97 , 98 ], thrombin [ 106 , 107 ], protein kinase C/mitogen-activated protein kinase and extracellular signal-regulated kinase signal [ 103 , 104 ], organic cation transporter [ 99 , 100 ], opioid receptors [ 46 , 78 , 79 , 80 ], phosphodiesterase [ 72 , 73 ], hyperpolarization-activated, cyclic nucleotide-gated cation channel [ 61 , 62 ], imidazoline receptors [ 63 ], endothelin receptor [ 74 ], cannabinoid receptors [ 75 ], sigma-1 receptors [ 76 , 77 ], orexin receptors [ 101 ], histamine receptors [ 102 ], ceramide-sphingosine 1-phosphate [ 105 ], chelate of oxalate [ 11 , 13 ], vascular endothelial growth factor [ 108 ], and others [ 48 , 54 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 …”