Sex differences in the affective-cognitive dimension of neuropathic pain: Insights from the spared nerve injury rat model

Over 40% of neuropathic pain patients experience mood and cognitive disturbances, often showing reduced response to analgesics, with most affected individuals being female. This highlights the critical role of biological sex in pain-related affective and cognitive disorders, making it essential to understand the emotional and cognitive circuits linked to pain for improving treatment strategies. However, research on sex differences in preclinical pain models is lacking. This study aimed to investigate these differences using the spared nerve injury (SNI) rat model, conducting a comprehensive series of behavioural tests over 100 days post-injury to identify key time points for observing sex-specific behaviours indicative of pain-related conditions. The findings revealed that female rats exhibited greater mechanical and cold hypersensitivity compared to males following nerve injury and showed earlier onset of depression-related behaviours, while males were more prone to anxiety, social, and memory-related alterations. Interestingly, by the 14th week post-injury, females displayed no signs of these emotional and cognitive impairments. Additionally, fluctuations in the oestrous cycle or changes in testosterone and oestradiol levels did not correlate with sex differences in pain sensitivity or negative affect. Recognizing the influence of biological sex on pain-induced affective and cognitive alterations, especially in later stages post- injury, is crucial for enhancing our understanding of this complex pain disorder. Perspective: This manuscript reports the relevance of long-term investigations of sex differences in chronic pain. It shows differential development of somatosensory sensitivity, negative affective states and cognitive impairments in males and females. It emphasizes the importance of including subjects of both sexes in the investigation of pain-related mechanisms and therapeutic management.