Time-dependent characterisation of sex differences in the chronic constriction injury (CCI) model of neuropathic pain.

Chronic neuropathic pain affects 7-10 % of the population and is often accompanied by emotional impairments, greatly reducing the quality of life of patients. Recently, we showed that in the chronic constriction injury (CCI) model of experimental neuropathic pain, female (but not male) rats showed a delayed but progressive development of mechanical and cold allodynia, which did not improve over time. In this work, we characterised the CCI-induced nociceptive and emotional impairments at earlier (2 weeks) and later (8 weeks) time points in both male and female rats. Both neuropathic males and females developed mechanical allodynia from week 1 onwards; however, males were shown to recover earlier at week 3, corroborated by sciatic nerve histopathology. Importantly, both males and females displayed cold allodynia throughout the experimental period (8 weeks). Regarding emotional impairments, males showed a more anxious and depressive phenotype than females, independently of CCI. Electrophysiological recordings suggest time-dependent changes in descending inhibition from the rostral ventromedial medulla (RVM) in response to CCI-induced neuropathic pain. Altogether, our results show the existence of sex-specific differences in the development and maintenance of CCI-induced nociceptive and emotional impairments, highlighting the need to include female subjects in the study of neuropathic pain mechanisms and treatments.