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

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.

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.

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.

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.