Investigation of chemotherapy-induced peripheral neuropathy-related behaviour in male and female rats: a role for the endocannabinoid system

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 N-acylethanolamines showed that PTX increased 2-arachidonoylglycerol, N-palmitoylethanolamide (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.

Publisher

University of Galway

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CC BY-NC-ND

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University of Galway Theses (PhD Theses)