Investigation of sexual dimorphism in an animal model of neuropathic pain: role of the endocannabinoid system
Boullon, Laura
Boullon, Laura
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Identifiers
http://hdl.handle.net/10379/17771
https://doi.org/10.13025/17602
https://doi.org/10.13025/17602
Repository DOI
Publication Date
2023-05-15
Type
Thesis
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Abstract
Although the presence of sexual dimorphism in the symptomatology of neuropathic pain is well-established, the neurobiology underlying sex differences in pain processing and modulation remains unclear. Gonadal hormones and neuroimmune signalling are the primary targets that have been investigated, however, sex differences in the physiology of other pain-related signalling pathways still remain unexplored. The endogenous cannabinoid system (ECS) plays a pivotal role in the modulation of nociception. Furthermore, sexual dimorphism in cannabinoid induced analgesia has been reported. However, the relevance of sex differences in the ECS physiology to pain is poorly understood. The overarching hypothesis of this thesis is that sex-specific alterations in the ECS promote sexual dimorphism in nociceptive behaviour. Investigating such sex dimorphic changes will facilitate an improved understanding of the pathophysiology of neuropathic pain in both sexes. It will permit identifying endocannabinoid-based pain-related biomarkers and the development of more effective analgesic tools in males and females. The results presented herein revealed sexually dimorphic development of mechanical and cold hypersensitivity, anxiodepressive behaviours and cognitive impairments in the spared nerve injury (SNI) rat model of neuropathic pain. Female injured rats exhibited greater nociceptive responsiveness to non-noxious stimuli and greater susceptibility to depression-related behaviours than males. In contrast, male injured rats developed anxiety-related behaviours and cognitive impairments, including altered spatial memory and sociability. Neuropathic pain-related behaviours were accompanied by sex-specific alteration of the ECS in regions involved in the descending modulation of nociception and emotional processing, including the prefrontal cortex, periaqueductal grey (PAG) and rostral ventromedial medulla. Subsequent chronic inhibition of the primary pathways for endocannabinoid degradation demonstrated a sexually dimorphic antinociceptive effect, with females exhibiting a greater reduction in nociceptive behaviour than males when systemically treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597. Biochemical analysis of neural substrates in the descending pain pathway pointed to N-acylethanolamines in the PAG as potentially implicated in this effect. Further analysis in the dorsolateral subcolumn of the PAG revealed sex differences in response to direct pharmacological activation of CB1, CB2 and PPAR suggesting that sex differences in the ECS in this region may underlie sexual dimorphism in the analgesic response to ECS modulation. In conclusion, these findings provide evidence of sex differences in the ECS neurobiology associated with nerve injury-induced persistent pain and emotional dysfunction. The present results also propose a critical role for the PAG in endocannabinoid-mediated sex-dimorphic antinociception. Altogether, the data presented in this thesis extend our current understanding of the neurobiology of sex differences and the therapeutic potential of the ECS in alleviating neuropathic pain related symptomatology in males and females
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Publisher
NUI Galway