An investigation on the role of oxytocin in chronic neuropathic pain in a Wistar Rat Model

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dc.contributor.advisorQulu, Lihleen_ZA
dc.contributor.advisorChetty, Seanen_ZA
dc.contributor.advisorAhmed Sherif, Isaen_ZA
dc.contributor.authorde Kock, Michaelaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.en_ZA
dc.date.accessioned2023-02-27T10:26:35Zen_ZA
dc.date.accessioned2023-05-18T07:02:11Zen_ZA
dc.date.available2023-02-27T10:26:35Zen_ZA
dc.date.available2023-05-18T07:02:11Zen_ZA
dc.date.issued2023-03en_ZA
dc.descriptionThesis (MMed)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH ABSTRACT: Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect with ineffective preventative and curative treatment, due to the condition's complexity perpetuated by the extensive central involvement, including the chronic disruption and subsequent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Currently, only Duloxetine has been recommended as effective treatment for CIPN, which has shown individual-dependent, short-term analgesic effects, with limiting adverse effects and poor bioavailability. The neuropeptide, oxytocin, may offer significant analgesic and anxiolytic potential, as it exerts central and peripheral attenuating effects on nociception. However, it is unknown whether the intervention administered in a model of CIPN is an effective therapeutic alternative. Materials and Methods The intervention was divided into two phases. Phase 1 aimed to induce CIPN in adult Wistar rats using the chemotherapeutic agent Paclitaxel. Mechanical (electronic von Frey filament) and thermal (acetone evaporation test and Hargreaves test) hypersensitivity testing was used to evaluate changes due to the neuropathic induction. Phase 2 consisted of a 14-day intervention period with saline (o.g.), Duloextine (o.g.), or oxytocin (i.n.) administered as treatment. Analgesic behavioural testing was assessed throughout the intervention period. Following the intervention, anxiety-like behaviour was assessed using the elevated plus maze (EPM) and light-dark box protocols. Analysis of peripheral plasma corticosterone, peripheral plasma oxytocin, and hypothalamic oxytocin concentrations were assessed using ELISA assays. Results The findings showed that we were able to successfully establish a model of chemotherapy-induced peripheral neuropathy during Phase 1, determined by the increase in mechanical and thermal nociceptive responses following chemotherapy administration. Furthermore, based on this finding, we were able to evaluate the effect of different treatments administered in the presence of CIPN. The animals treated with oxytocin displayed a significant improvement in mechanical sensitivity over the intervention phase, indicative of an improvement in nociceptive tolerance in the presence of neuropathic pain. Animals that received Paclitaxel and treated with oxytocin also displayed significantly greater explorative behaviour during the EPM, indicative of a reduced presence of anxiety-like behavior. Conclusion Our results support the hypothesis that intranasally administered oxytocin may augment the analgesic and anxiolytic effects of duloxetine in a chemotherapy-induced peripheral neuropathy model in a Wistar rat. Administered in conjunction, oxytocin and duloxetine may provide enhanced therapeutic effects in the treatment of CIPN. Further research is necessary to establish optimal treatment and dosage requirements.en_ZA
dc.description.abstractAFRIKAANS OPSOMMING: Inleiding: Chemoterapie-geïnduseerde perifere neuropatie (CIPN) is ‘n dosering-beperkte newe effek, met ondoeltreffende voorkomende en genesende behandeling. Dit is as gevolg van die toestand se kompleksiteit, wat vererger word deur die omvattende sentrale meewerking, wat chroniese ontwrigting en daaropvolgende wanregulering van die hipotalamus-pituïtêre-bynieras (HPA) insluit. Tans word slegs Duloxetine aanbeveel as effektiewe behandeling vir CIPN, wat individu-afhanklike, korttermyn pynstillende effekte getoon het. Dit het egter beperkende nadelige effekte en swak biobeskikbaarheid. Die neuropeptied, oksitosien, kan aansienlike pynstillende en anxiolitiese potensiaal bied, aangesien dit sentrale en perifere verlaging van nosisepsie tot gevolg het. Dit is egter onbekend of die intervensie wat in 'n model van CIPN toegedien word, 'n effektiewe terapeutiese alternatief is. Materiale en Metodes: Die intervensie is in twee fases verdeel. Fase 1 het ten doel gehad om CIPN in volwasse Wistar-rotte te induseer deur die chemoterapeutiese middel Paclitaxel te gebruik. Meganiese (elektroniese von Frey filament) en termiese (asetoon verdampingstoets en Hargreaves toets) hipersensitiwiteitstoetse is gebruik om veranderinge as gevolg van die neuropatiese induksie te evalueer. Fase 2 het bestaan uit 'n 14-dae intervensieperiode met saline (o.g.), Duloextine (o.g.) of oksitosien (i.n.) toegedien as behandeling. Analgetiese gedragstoetsing is deur die intervensieperiode geevalueer. Na die intervensie is angs gedrag geevalueer deur gebruik te maak van die verhoogde plus doolhof (EPM) en lig-donker boks protokolle. Ontleding van perifere plasma kortikosteroon, perifere plasma oksitosien en hipotalamus oksitosien konsentrasies is geassesseer met behulp van ELISA toetse. Resultate: Die bevindinge het getoon dat ons 'n model van chemoterapie-geïnduseerde perifere neuropatie suksesvol kon vestig tydens Fase 1. Verder, gebaseer op hierdie bevinding, was ons in staat om die effek van verskillende behandelings wat in die teenwoordigheid van CIPN toegedien is, te evalueer. Die bevindings het getoon dat ons 'n model van chemoterapie-geïnduseerde perifere neuropatie tydens Fase 1 suksesvol kon vestig. Die diere wat met oksitosien behandel is, het 'n aansienlike verbetering in meganiese sensitiwiteit oor die intervensiefase getoon, wat dui op 'n verbetering in nosiseptiewe toleransie in die teenwoordigheid van neuropatiese pyn. Diere wat Paclitaxel ontvang en met oksitosien behandel is, het ook aansienlik groter verkennings gedrag tydens die EPM getoon, wat dui op 'n verminderde teenwoordigheid van angsagtige gedrag. Afsluiting: Ons resultate ondersteun die hipotese dat intranasaal toegediende oksitosien die pynstillende en anxiolitiese effekte van duloksetien kan versterk in 'n chemoterapiegeïnduseerde perifere neuropatie-model in 'n Wistar-rot. As dit saam toegedien word, kan oksitosien en duloksetien verbeterde terapeutiese effekte in die behandeling van CIPN bied. Verdere navorsing is nodig om optimale behandeling en dosisvereistes vas te stel.af_ZA
dc.description.versionMastersen_ZA
dc.format.extent128 pages : illustrationsen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/127057en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshCancer -- Chemotherapy -- Complicationsen_ZA
dc.subject.lcshAnalgesicsen_ZA
dc.subject.lcshChemotherapy-induced peripheral neuropathyen_ZA
dc.subject.lcshOxytocinen_ZA
dc.subject.lcshHypothalamic-pituitary-adrenal axisen_ZA
dc.subject.lcshTranquilizing drugsen_ZA
dc.subject.lcshPeripheral neuropathyen_ZA
dc.subject.lcshWistar Rat Modelen_ZA
dc.titleAn investigation on the role of oxytocin in chronic neuropathic pain in a Wistar Rat Modelen_ZA
dc.typeThesisen_ZA
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