Papers of the Week

Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following re-injury in adulthood. Spinal microglia contribute to this persistent effect and microglial inhibition at the time of adult re-incision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult re-incision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation () and transformation to a reactive phenotype (). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to re-incision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following re-incision in adulthood was prevented in males but unaffected in females. Similarly, re-incision induced and gene expression was downregulated in males, but not in females following neonatal incision with minocycline. To evaluate the distribution of re-incision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was re-incised, and was increased following prior incision at ipsilateral, but not contralateral sites; supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state spans developmental stages. Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances re-injury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on re-injury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in pre-clinical studies.