Sex Differences in Markers of Neuronal Adaptation in the Medullary Dorsal Horn During the Development of Orofacial Neuropathic Pain

Chronic trigeminal neuropathic pain is caused by a lesion, damage, or trauma to the trigeminal sensory system. The pain affects female individuals with higher incidence and greater severity compared with males. Despite a strong sex bias in this clinical condition, the majority of preclinical experimental studies of trigeminal neuropathic pain have been conducted in males. This study investigated sex differences in the number of ΔFosB and FosB immunoreactive cells, as markers of neuronal adaptation following infraorbital nerve chronic constriction injury (ION-CCI). Sex differences in ΔFosB and FosB expression were identified in infra-orbital recipient regions of laminae I-II of the medullary dorsal horn during the post-injury period. Three phases of altered expression were identified following ION-CCI: (1) an early phase 2 days after injury, (2) a transitional phase (7-14 days), and (3) a late phase (28+ days). Nerve-injured female rats had consistently lower levels of ΔFosB immunoreactive cells when compared with males and showed increased FosB expression during the early phase. In contrast, in males, the number of ΔFosB immunoreactive cells decreased significantly from the early phase to the transitional phase post-injury. However, by the late phase, ΔFosB expression in the superficial laminae of the medullary dorsal horn was significantly higher than in females. These data suggest that cellular adaptation in neurons in laminae I-II of the medullary dorsal horn in males is much greater than that in females, revealing one location at which the sex differences seen in the incidence and severity of trigeminal neuropathic pain might be mediated.