Early-Life Iron Deficiency Persistently Alters Nociception in Developing Mice

Clinical association studies have identified early-life iron deficiency (ID) as a risk factor for the development of chronic pain. While preclinical studies have shown that early-life ID persistently alters neuronal function in the central nervous system, a causal relationship between early-life ID and chronic pain has yet to be established. We sought to address this gap in knowledge by characterizing pain sensitivity in developing male and female C57Bl/6 mice that were exposed to dietary ID during early life. Dietary iron was reduced by ∼90% in dams between gestational day 14 and postnatal day (P)10, with dams fed an ingredient-matched, iron-sufficient diet serving as controls. While cutaneous mechanical and thermal withdrawal thresholds were not altered during the acute ID state at P10 and P21, ID mice were more sensitive to mechanical pressure at P21 independent of sex. During adulthood, when signs of ID had resolved, mechanical and thermal thresholds were similar between early-life ID and control groups, although male and female ID mice displayed increased thermal tolerance at an aversive (45 °C) temperature. Interestingly, while adult ID mice showed decreased formalin-induced nocifensive behaviors, they showed exacerbated mechanical hypersensitivity and increased paw guarding in response to hindpaw incision in both sexes. Collectively, these results suggest that early-life ID elicits persistent changes in nociceptive processing and appears capable of priming developing pain pathways. PERSPECTIVE: This study provides novel evidence that early-life ID evokes sex-independent effects on nociception in developing mice, including an exacerbation of postsurgical pain during adulthood. These findings represent a critical first step towards the long-term goal of improving health outcomes for pain patients with a prior history of ID.