Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity

Oxaliplatin andpaclitaxelareconsideredcentralcomponentsinthetreatmentofcolorectalandbreast cancer,respectively.Thedevelopmentofneuropathyduringchronictreatmentrepresentsthemajor dose-limiting sideeffectthatleadstodiscontinuationorinterruptionoftherapies.Themanagementof neuropathyisachallengetoindividuateinnovativetherapeuticstrategiesbasedonnewtargetsand correct routesofadministration.Weevaluatedthehypersensitivityrelievereffectofdifferentopioid receptoragonistsinratmodelsofoxaliplatinandpaclitaxel-inducedneuropathy.Compoundswere spinally infusedbyintrathecalcatheter.Inoxaliplatin-treatedrats,0.3nmolmorphineinducedthere- version ofthemechanicalhypersensitivity(Paw-pressuretest),nociceptin/orphaninFQ(N/OFQ;0.3– 3 nmol)significantly increasedthepainthresholdwithoutreachingthevaluesofthecontrolanimals. The N/OFQpeptide(NOP)receptorfullagonistUFP-112revertedpainthresholdalterationsatlower dosage (0.1nmol)vsmorphineandN/OFQ,thepartialagonistUFP-113(0.1–1 nmol)wassimilartoN/ OFQ. Thehigherefficacy ofmorphinevsN/OFQwashighlightedalsoinpaclitaxel-treatedrats.The mechanical hypersensitivitywasfullyrevertedby0.1nmolUFP-112andUFP-113.Inconclusion,in- trathecal μ opioid peptide(MOP)andNOPreceptoragonistsrelievedchemotherapy-inducedneuropathic pain. Thesyntheticpeptidesshowedvaluablepotencyandefficacy suggestingtheNOPsystemasan exploitabletarget.