{"id":{"repo_id":"cadiz","oai_identifier":"oai:rodin.uca.es:10498/39690"},"canonical_url":"https://search.dev.ndltd.org/etd/cadiz/oai:rodin.uca.es:10498/39690","repository":{"repo_id":"cadiz","name":"Universidad de Cadiz","base_url":"https://rodin.uca.es/oai/request"},"display":{"title":"Investigation of chemotherapy-induced peripheral neuropathy-related behaviour in male and female ratsa role for the endocannabinoid system","abstract":"Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and debilitating side effect of cancer treatment, often persisting for months after therapy cessation and profoundly impairing quality of life. Among chemotherapeutic agents, paclitaxel (PTX) stands out for its broad clinical use across several cancer types, and its use is strongly associated with the development of chronic neuropathic pain, particularly in women. This pain represents a clinically significant component of CIPN, yet pharmacological treatments to manage it effectively remain limited, underscoring the need to elucidate the underlying neurobiological mechanisms. Accumulating evidence suggests that the endocannabinoid system represents a promising therapeutic target for CIPN, given its key role in pain regulation and the favourable tolerability profile of cannabinoids or endocannabinoid system modulators in patients with chronic pain. Both pain circuitry and the endocannabinoid system exhibit sexual dimorphisms. Therefore, the work presented in this thesis tested the hypothesis that administration of the chemotherapeutic agent PTX induces changes in somatosensory pain responding-, anxiety-, depression-, and cognition-related behaviour in rats, with associated alterations in the endocannabinoid system. We propose that these changes are sensitive to pharmacological modulation of the endocannabinoid system and that these effects will exhibit sexual dimorphisms. Behavioural characterisation of the PTX-induced peripheral neuropathy model revealed robust somatosensory hypersensitivity to mechanical and cold, but not heat, stimuli in both sexes. These sensory alterations were of a similar magnitude in males and females and occurred in the absence of anxiety-, depression-, or cognition-related changes, indicating a selective impact of PTX on nociceptive behaviour. Post-mortem analysis of endocannabinoids and related Nacylethanolamines showed that PTX increased 2-arachidonoylglycerol, Npalmitoylethanolamide (PEA) and N-oleoylethanolamide levels in the amygdala of both male and female animals. Next, we assessed whether this pain phenotype was sensitive to acute pharmacological modulation of endocannabinoid signalling via three complementary approaches: (1) inhibition of fatty acid amide hydrolase (FAAH), (2) antagonism of the transient receptor potential vanilloid 1 (TRPV1) channel, and (3) dual FAAH inhibition/TRPV1 antagonism. All treatments, administered systemically, significantly reduced PTX-induced mechanical hypersensitivity, while the dual FAAH inhibition/TRPV1 antagonist also attenuated cold hypersensitivity. Only the FAAH inhibitor produced region-specific increases in levels of the AEA, PEA, and OEA, within pain-related brain regions, the spinal cord, and the plasma, supporting a role for FAAH substrates in modulation of nociceptive hypersensitivity due to CIPN. Building on these findings and given the well-established role of the midbrain periaqueductal grey (PAG) in descending pain control and the neurochemical alterations identified in the systemic study, subsequent experiments showed that microinjection of the FAAH inhibitor directly into the dorsolateral periaqueductal grey (dlPAG) attenuated PTX-induced mechanical, but not cold, hypersensitivity. This was associated with increased levels of PEA in the dlPAG, suggesting that a deficit in endocannabinoid system signalling within this brain region may, at least in part, underlie PTX-induced nociceptive behaviour. Moreover, acute restraint stress failed to elicit stress-induced analgesia in PTX-treated animals, suggesting alterations in descending inhibitory control in this model of CIPN. Overall, this work provides new insights into the behavioural consequences and neurobiological substrates of PTX-induced peripheral neuropathy, identifying the endocannabinoid system as a promising therapeutic target for the management of neuropathic pain in this model of CIPN.","abstract_html":"Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and debilitating side effect of cancer treatment, often persisting for months after therapy cessation and profoundly impairing quality of life. Among chemotherapeutic agents, paclitaxel (PTX) stands out for its broad clinical use across several cancer types, and its use is strongly associated with the development of chronic neuropathic pain, particularly in women. This pain represents a clinically significant component of CIPN, yet pharmacological treatments to manage it effectively remain limited, underscoring the need to elucidate the underlying neurobiological mechanisms. Accumulating evidence suggests that the endocannabinoid system represents a promising therapeutic target for CIPN, given its key role in pain regulation and the favourable tolerability profile of cannabinoids or endocannabinoid system modulators in patients with chronic pain. Both pain circuitry and the endocannabinoid system exhibit sexual dimorphisms. Therefore, the work presented in this thesis tested the hypothesis that administration of the chemotherapeutic agent PTX induces changes in somatosensory pain responding-, anxiety-, depression-, and cognition-related behaviour in rats, with associated alterations in the endocannabinoid system. We propose that these changes are sensitive to pharmacological modulation of the endocannabinoid system and that these effects will exhibit sexual dimorphisms. Behavioural characterisation of the PTX-induced peripheral neuropathy model revealed robust somatosensory hypersensitivity to mechanical and cold, but not heat, stimuli in both sexes. These sensory alterations were of a similar magnitude in males and females and occurred in the absence of anxiety-, depression-, or cognition-related changes, indicating a selective impact of PTX on nociceptive behaviour. Post-mortem analysis of endocannabinoids and related Nacylethanolamines showed that PTX increased 2-arachidonoylglycerol, Npalmitoylethanolamide (PEA) and N-oleoylethanolamide levels in the amygdala of both male and female animals. Next, we assessed whether this pain phenotype was sensitive to acute pharmacological modulation of endocannabinoid signalling via three complementary approaches: (1) inhibition of fatty acid amide hydrolase (FAAH), (2) antagonism of the transient receptor potential vanilloid 1 (TRPV1) channel, and (3) dual FAAH inhibition/TRPV1 antagonism. All treatments, administered systemically, significantly reduced PTX-induced mechanical hypersensitivity, while the dual FAAH inhibition/TRPV1 antagonist also attenuated cold hypersensitivity. Only the FAAH inhibitor produced region-specific increases in levels of the AEA, PEA, and OEA, within pain-related brain regions, the spinal cord, and the plasma, supporting a role for FAAH substrates in modulation of nociceptive hypersensitivity due to CIPN. Building on these findings and given the well-established role of the midbrain periaqueductal grey (PAG) in descending pain control and the neurochemical alterations identified in the systemic study, subsequent experiments showed that microinjection of the FAAH inhibitor directly into the dorsolateral periaqueductal grey (dlPAG) attenuated PTX-induced mechanical, but not cold, hypersensitivity. This was associated with increased levels of PEA in the dlPAG, suggesting that a deficit in endocannabinoid system signalling within this brain region may, at least in part, underlie PTX-induced nociceptive behaviour. Moreover, acute restraint stress failed to elicit stress-induced analgesia in PTX-treated animals, suggesting alterations in descending inhibitory control in this model of CIPN. Overall, this work provides new insights into the behavioural consequences and neurobiological substrates of PTX-induced peripheral neuropathy, identifying the endocannabinoid system as a promising therapeutic target for the management of neuropathic pain in this model of CIPN.","abstract_has_math":false,"creators":["Di Marino, Chiara"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Berrocoso Domínguez, Esther María","Finn, David P."],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026","date_published":"2026","updated_at":"2026-07-24T01:29:34Z","subjects":[],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10498/39690","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Berrocoso Domínguez, Esther María","Finn, David P."]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Neurociencias"]},{"key":"dc:creator","label":"Author","values":["Di Marino, Chiara"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-06-03T07:47:12Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-06-03T07:47:12Z"]},{"key":"dc:date.issued","label":"Date","values":["2026"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10498/39690"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and debilitating side effect of cancer treatment, often persisting for months after therapy cessation and profoundly impairing quality of life. Among chemotherapeutic agents, paclitaxel (PTX) stands out for its broad clinical use across several cancer types, and its use is strongly associated with the development of chronic neuropathic pain, particularly in women. This pain represents a clinically significant component of CIPN, yet pharmacological treatments to manage it effectively remain limited, underscoring the need to elucidate the underlying neurobiological mechanisms. Accumulating evidence suggests that the endocannabinoid system represents a promising therapeutic target for CIPN, given its key role in pain regulation and the favourable tolerability profile of cannabinoids or endocannabinoid system modulators in patients with chronic pain. Both pain circuitry and the endocannabinoid system exhibit sexual dimorphisms. Therefore, the work presented in this thesis tested the hypothesis that administration of the chemotherapeutic agent PTX induces changes in somatosensory pain responding-, anxiety-, depression-, and cognition-related behaviour in rats, with associated alterations in the endocannabinoid system. We propose that these changes are sensitive to pharmacological modulation of the endocannabinoid system and that these effects will exhibit sexual dimorphisms. Behavioural characterisation of the PTX-induced peripheral neuropathy model revealed robust somatosensory hypersensitivity to mechanical and cold, but not heat, stimuli in both sexes. These sensory alterations were of a similar magnitude in males and females and occurred in the absence of anxiety-, depression-, or cognition-related changes, indicating a selective impact of PTX on nociceptive behaviour. Post-mortem analysis of endocannabinoids and related Nacylethanolamines showed that PTX increased 2-arachidonoylglycerol, Npalmitoylethanolamide (PEA) and N-oleoylethanolamide levels in the amygdala of both male and female animals. Next, we assessed whether this pain phenotype was sensitive to acute pharmacological modulation of endocannabinoid signalling via three complementary approaches: (1) inhibition of fatty acid amide hydrolase (FAAH), (2) antagonism of the transient receptor potential vanilloid 1 (TRPV1) channel, and (3) dual FAAH inhibition/TRPV1 antagonism. All treatments, administered systemically, significantly reduced PTX-induced mechanical hypersensitivity, while the dual FAAH inhibition/TRPV1 antagonist also attenuated cold hypersensitivity. Only the FAAH inhibitor produced region-specific increases in levels of the AEA, PEA, and OEA, within pain-related brain regions, the spinal cord, and the plasma, supporting a role for FAAH substrates in modulation of nociceptive hypersensitivity due to CIPN. Building on these findings and given the well-established role of the midbrain periaqueductal grey (PAG) in descending pain control and the neurochemical alterations identified in the systemic study, subsequent experiments showed that microinjection of the FAAH inhibitor directly into the dorsolateral periaqueductal grey (dlPAG) attenuated PTX-induced mechanical, but not cold, hypersensitivity. This was associated with increased levels of PEA in the dlPAG, suggesting that a deficit in endocannabinoid system signalling within this brain region may, at least in part, underlie PTX-induced nociceptive behaviour. Moreover, acute restraint stress failed to elicit stress-induced analgesia in PTX-treated animals, suggesting alterations in descending inhibitory control in this model of CIPN. Overall, this work provides new insights into the behavioural consequences and neurobiological substrates of PTX-induced peripheral neuropathy, identifying the endocannabinoid system as a promising therapeutic target for the management of neuropathic pain in this model of CIPN.","La neuropatía periférica inducida por quimioterapia (CIPN) es un efecto secundario frecuente y debilitante del tratamiento oncológico, que suele persistir durante meses tras finalizar la terapia y deteriora profundamente la calidad de vida. Entre los agentes quimioterapéuticos, el paclitaxel (PTX) destaca por su amplio uso clínico en varios tipos de cáncer y su fuerte asociación con el dolor neuropático crónico, especialmente en mujeres. Este fenotipo doloroso constituye un componente clínicamente relevante de la CIPN, aunque los tratamientos farmacológicos eficaces siguen siendo limitados, lo que subraya la necesidad de esclarecer los mecanismos neurobiológicos subyacentes. La evidencia acumulada sugiere que el sistema endocannabinoide es una diana terapéutica prometedora debido a su papel clave en la regulación del dolor y al perfil de tolerabilidad de los cannabinoides o moduladores del sistema endocannabinoide en pacientes con dolor crónico. Tanto el dolor como el sistema endocannabinoide presentan dimorfismo sexual. Por ello, el trabajo presentado en esta tesis evaluó la hipótesis de que la administración del agente quimioterapéutico PTX induce conductas relacionadas con dolor, ansiedad, depresión y déficits cognitivos en ratas, junto con alteraciones asociadas en el sistema endocannabinoide sensibles a la modulación farmacológica, y que estos efectos muestran dimorfismo sexual. La caracterización conductual del modelo de neuropatía periférica inducida por PTX reveló una marcada hipersensibilidad somatosensorial a estímulos mecánicos y fríos, pero no térmicos, en ambos sexos. Estas alteraciones sensoriales fueron de magnitud similar en machos y hembras y se produjeron en ausencia de cambios relacionados con ansiedad, depresión o cognición, indicando un impacto selectivo del PTX sobre la conducta nociceptiva. Análisis post mortem de endocannabinoides y N-aciletanolaminas mostró que el PTX incrementó los niveles de 2-araquidonoil glicerol, N-palmitoiletanolamina (PEA) y N-oleoiletanolamina en la amígdala de machos y hembras. A partir de estos hallazgos, para determinar si este fenotipo doloroso era sensible a la modulación farmacológica aguda de la señalización endocannabinoide, se emplearon tres enfoques complementarios: inhibición de la amida hidrolasa de ácidos grasos (FAAH), antagonismo del canal receptor transitorio vanilloide 1 (TRPV1) y la combinación dual de inhibición de FAAH/antagonismo de TRPV1. Todos los tratamientos administrados de forma sistémica aliviaron significativamente la hipersensibilidad mecánica inducida por PTX, mientras que el inhibidor dual FAAH/TRPV1 también atenuó la hipersensibilidad térmica al frío. Solo el inhibidor de FAAH produjo aumentos específicos de los niveles del endocannabinoide anandamida y N-aciletanolamidas en regiones cerebrales implicadas en el dolor, en la médula espinal y en el plasma, apoyando un papel de los sustratos de FAAH en la modulación de la CIPN. Basándose en estos hallazgos y dada la implicación establecida de la sustancia gris periacueductal (PAG) en el control descendente del dolor y las alteraciones neuroquímicas identificadas en el estudio sistémico, experimentos adicionales demostraron que la microinyección del inhibidor de FAAH en la región dorsolateral de la sustancia gris periacueductal (dlPAG) atenuó la hipersensibilidad mecánica, pero no la fría, inducida por PTX, un efecto asociado con un aumento de los niveles de PEA. Esto sugiere que un déficit en la señalización del sistema endocannabinoide en la región dlPAG podría contribuir, al menos en parte, a la conducta nociceptiva inducida por PTX. Además, el estrés por restricción agudo no provocó analgesia en los animales tratados con PTX, lo que sugiere alteraciones en el control inhibitorio descendente en este modelo de CIPN. En conjunto, este trabajo aporta nuevos conocimientos sobre las consecuencias conductuales y los sustratos neurobiológicos de la neuropatía periférica inducida por PTX, identificando el sistema endocannabinoide como una diana terapéutica prometedora para el tratamiento del dolor neuropático en este modelo de CIPN."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Investigation of chemotherapy-induced peripheral neuropathy-related behaviour in male and female ratsa role for the endocannabinoid system"]}]}],"canonical_facts":{"dc:contributor.advisor":["Berrocoso Domínguez, Esther María","Finn, David P."],"dc:contributor.other":["Neurociencias"],"dc:creator":["Di Marino, Chiara"],"dc:date.accessioned":["2026-06-03T07:47:12Z"],"dc:date.available":["2026-06-03T07:47:12Z"],"dc:date.issued":["2026"],"dc:description.abstract":["Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and debilitating side effect of cancer treatment, often persisting for months after therapy cessation and profoundly impairing quality of life. Among chemotherapeutic agents, paclitaxel (PTX) stands out for its broad clinical use across several cancer types, and its use is strongly associated with the development of chronic neuropathic pain, particularly in women. This pain represents a clinically significant component of CIPN, yet pharmacological treatments to manage it effectively remain limited, underscoring the need to elucidate the underlying neurobiological mechanisms. Accumulating evidence suggests that the endocannabinoid system represents a promising therapeutic target for CIPN, given its key role in pain regulation and the favourable tolerability profile of cannabinoids or endocannabinoid system modulators in patients with chronic pain. Both pain circuitry and the endocannabinoid system exhibit sexual dimorphisms. Therefore, the work presented in this thesis tested the hypothesis that administration of the chemotherapeutic agent PTX induces changes in somatosensory pain responding-, anxiety-, depression-, and cognition-related behaviour in rats, with associated alterations in the endocannabinoid system. We propose that these changes are sensitive to pharmacological modulation of the endocannabinoid system and that these effects will exhibit sexual dimorphisms. Behavioural characterisation of the PTX-induced peripheral neuropathy model revealed robust somatosensory hypersensitivity to mechanical and cold, but not heat, stimuli in both sexes. These sensory alterations were of a similar magnitude in males and females and occurred in the absence of anxiety-, depression-, or cognition-related changes, indicating a selective impact of PTX on nociceptive behaviour. Post-mortem analysis of endocannabinoids and related Nacylethanolamines showed that PTX increased 2-arachidonoylglycerol, Npalmitoylethanolamide (PEA) and N-oleoylethanolamide levels in the amygdala of both male and female animals. Next, we assessed whether this pain phenotype was sensitive to acute pharmacological modulation of endocannabinoid signalling via three complementary approaches: (1) inhibition of fatty acid amide hydrolase (FAAH), (2) antagonism of the transient receptor potential vanilloid 1 (TRPV1) channel, and (3) dual FAAH inhibition/TRPV1 antagonism. All treatments, administered systemically, significantly reduced PTX-induced mechanical hypersensitivity, while the dual FAAH inhibition/TRPV1 antagonist also attenuated cold hypersensitivity. Only the FAAH inhibitor produced region-specific increases in levels of the AEA, PEA, and OEA, within pain-related brain regions, the spinal cord, and the plasma, supporting a role for FAAH substrates in modulation of nociceptive hypersensitivity due to CIPN. Building on these findings and given the well-established role of the midbrain periaqueductal grey (PAG) in descending pain control and the neurochemical alterations identified in the systemic study, subsequent experiments showed that microinjection of the FAAH inhibitor directly into the dorsolateral periaqueductal grey (dlPAG) attenuated PTX-induced mechanical, but not cold, hypersensitivity. This was associated with increased levels of PEA in the dlPAG, suggesting that a deficit in endocannabinoid system signalling within this brain region may, at least in part, underlie PTX-induced nociceptive behaviour. Moreover, acute restraint stress failed to elicit stress-induced analgesia in PTX-treated animals, suggesting alterations in descending inhibitory control in this model of CIPN. Overall, this work provides new insights into the behavioural consequences and neurobiological substrates of PTX-induced peripheral neuropathy, identifying the endocannabinoid system as a promising therapeutic target for the management of neuropathic pain in this model of CIPN.","La neuropatía periférica inducida por quimioterapia (CIPN) es un efecto secundario frecuente y debilitante del tratamiento oncológico, que suele persistir durante meses tras finalizar la terapia y deteriora profundamente la calidad de vida. Entre los agentes quimioterapéuticos, el paclitaxel (PTX) destaca por su amplio uso clínico en varios tipos de cáncer y su fuerte asociación con el dolor neuropático crónico, especialmente en mujeres. Este fenotipo doloroso constituye un componente clínicamente relevante de la CIPN, aunque los tratamientos farmacológicos eficaces siguen siendo limitados, lo que subraya la necesidad de esclarecer los mecanismos neurobiológicos subyacentes. La evidencia acumulada sugiere que el sistema endocannabinoide es una diana terapéutica prometedora debido a su papel clave en la regulación del dolor y al perfil de tolerabilidad de los cannabinoides o moduladores del sistema endocannabinoide en pacientes con dolor crónico. Tanto el dolor como el sistema endocannabinoide presentan dimorfismo sexual. Por ello, el trabajo presentado en esta tesis evaluó la hipótesis de que la administración del agente quimioterapéutico PTX induce conductas relacionadas con dolor, ansiedad, depresión y déficits cognitivos en ratas, junto con alteraciones asociadas en el sistema endocannabinoide sensibles a la modulación farmacológica, y que estos efectos muestran dimorfismo sexual. La caracterización conductual del modelo de neuropatía periférica inducida por PTX reveló una marcada hipersensibilidad somatosensorial a estímulos mecánicos y fríos, pero no térmicos, en ambos sexos. Estas alteraciones sensoriales fueron de magnitud similar en machos y hembras y se produjeron en ausencia de cambios relacionados con ansiedad, depresión o cognición, indicando un impacto selectivo del PTX sobre la conducta nociceptiva. Análisis post mortem de endocannabinoides y N-aciletanolaminas mostró que el PTX incrementó los niveles de 2-araquidonoil glicerol, N-palmitoiletanolamina (PEA) y N-oleoiletanolamina en la amígdala de machos y hembras. A partir de estos hallazgos, para determinar si este fenotipo doloroso era sensible a la modulación farmacológica aguda de la señalización endocannabinoide, se emplearon tres enfoques complementarios: inhibición de la amida hidrolasa de ácidos grasos (FAAH), antagonismo del canal receptor transitorio vanilloide 1 (TRPV1) y la combinación dual de inhibición de FAAH/antagonismo de TRPV1. Todos los tratamientos administrados de forma sistémica aliviaron significativamente la hipersensibilidad mecánica inducida por PTX, mientras que el inhibidor dual FAAH/TRPV1 también atenuó la hipersensibilidad térmica al frío. Solo el inhibidor de FAAH produjo aumentos específicos de los niveles del endocannabinoide anandamida y N-aciletanolamidas en regiones cerebrales implicadas en el dolor, en la médula espinal y en el plasma, apoyando un papel de los sustratos de FAAH en la modulación de la CIPN. Basándose en estos hallazgos y dada la implicación establecida de la sustancia gris periacueductal (PAG) en el control descendente del dolor y las alteraciones neuroquímicas identificadas en el estudio sistémico, experimentos adicionales demostraron que la microinyección del inhibidor de FAAH en la región dorsolateral de la sustancia gris periacueductal (dlPAG) atenuó la hipersensibilidad mecánica, pero no la fría, inducida por PTX, un efecto asociado con un aumento de los niveles de PEA. Esto sugiere que un déficit en la señalización del sistema endocannabinoide en la región dlPAG podría contribuir, al menos en parte, a la conducta nociceptiva inducida por PTX. Además, el estrés por restricción agudo no provocó analgesia en los animales tratados con PTX, lo que sugiere alteraciones en el control inhibitorio descendente en este modelo de CIPN. En conjunto, este trabajo aporta nuevos conocimientos sobre las consecuencias conductuales y los sustratos neurobiológicos de la neuropatía periférica inducida por PTX, identificando el sistema endocannabinoide como una diana terapéutica prometedora para el tratamiento del dolor neuropático en este modelo de CIPN."],"dc:format":["application/pdf"],"dc:identifier.uri":["http://hdl.handle.net/10498/39690"],"dc:language.iso":["eng"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:title":["Investigation of chemotherapy-induced peripheral neuropathy-related behaviour in male and female ratsa role for the endocannabinoid system"],"dc:type":["doctoral thesis"]},"updated_at":"2026-07-24T01:29:34Z"}