Sex differences in the impact of nerve injury on locus coeruleus function and behaviour in mice

ABSTRACT: Chronic pain often coexists with anxiety and depression, particularly in women. The locus coeruleus (LC), a noradrenergic nucleus, modulates pain and emotional states and shows sex-specific structural and functional properties in preclinical studies. Moreover, clinical evidence indicates sex differences in the experience of chronic pain and its emotional impact. These findings highlight the need to explore the LC mechanisms underlying sex-dependent differences in chronic pain. In this study, we examined the sex-specific role of the LC in chronic pain and its emotional and cognitive consequences. Male and female mice exposed to the chronic constriction injury (CCI) model (2/3 and 7/11 weeks postinjury) were evaluated for sensory responses (von Frey, acetone, plantar tests), anxiety-like behavior (open field), depressive-like behavior (tail suspension test, forced swimming test), and cognitive performance (novel object recognition test). We also analyzed the number, somatodendritic volume, and electrophysiological properties of noradrenergic LC neurons. Finally, we assessed the effects of chemogenetic LC inhibition on anxiety- and depressive-like behavior, as well as fear responses. Nerve injury induced immediate sensory hypersensitivity in both sexes. Depressive-like behavior and cognitive deficits appeared only after prolonged injury. Notably, anxiety-like behavior and enhanced fear conditioning were exclusive to CCI male mice and correlated with LC-specific changes: increased cell number and somatodendritic volume, as well as heightened excitability. In female mice, however, neuronal excitability was reduced. Chemogenetic LC inhibition reversed anxiety- and depressive-like behaviors and fear responses only in CCI male mice. These findings show that neuropathic pain elicits sex-specific emotional and neural responses in the LC, highlighting the need for sex-specific approaches when investigating LC function and developing targeted interventions.