Investigation of sexual dimorphism in an animal model of neuropathic pain: role of the endocannabinoid system
Date
2023-05-15Embargo Date
2024-11-12
Author
Boullon, Laura
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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