Distinct and Shared Brain-Wide Activation Patterns in Mouse Models of Inflammatory and Neuropathic Pain.

Objective: Inflammatory and neuropathic pain arise from different peripheral insults but share nociceptive and affective features. Whether they recruit common or model-specific brain-wide activation patterns remains unclear. We compared regional neuronal activation and interregional co-activation in mouse models of these pain states. Methods: Inflammatory pain was induced using complete Freund's adjuvant (CFA), whereas neuropathic pain was induced by spared nerve injury (SNI). Nociceptive, anxiety-like, and depression-like behaviors were assessed. Recent neuronal activation was quantified by c-Fos immunohistochemistry across 50 subregions within seven major brain divisions. Images were registered to the Allen Mouse Brain Atlas. Hierarchical clustering and interregional c-Fos covariance analysis were used to compare activation patterns and identify candidate network hubs. Results: Both models developed persistent nociceptive hypersensitivity and anxiety-like behavior, without detectable depression-like behavior. CFA increased c-Fos expression in 28 regions and SNI in 34 regions, with 20 regions commonly activated across both models. These shared regions encompassed sensory, affective, and motivational systems. The CFA co-activation network showed relative prominence of thalamic and hypothalamic hubs, including the paraventricular thalamus and dorsomedial hypothalamus. In contrast, SNI exhibited a more distributed sensory and corticolimbic hub profile involving the primary somatosensory cortex, secondary motor cortex, central amygdala, and hippocampal CA3. Model-associated activation was also detected in comparatively understudied regions, including the dorsal endopiriform, lateral septal, and basomedial amygdalar nuclei. Conclusion: CFA and SNI were associated with overlapping regional recruitment but differently organized brain-wide c-Fos co-activation patterns. Although these descriptive patterns do not establish directed connectivity or causal circuit function, they identify candidate regions and network organizations for mechanistic studies of chronic pain.