Preadolescent Morphine Exposure Produces Sexually Dimorphic Alterations in Adult Rat Spinal Nociceptive Processing

Opioids are widely used for paediatric pain management; however, the long-term impacts of opioid exposure during later stages of neural development on spinal nociceptive circuitry remain unclear. We investigated whether repeated morphine exposure during preadolescence produces alterations in dorsal horn (DH) responses and sensory processing in adulthood. Male and female rats received morphine (3 mg/kg, twice daily) or saline from postnatal days 21-28. Mechanical withdrawal thresholds were assessed longitudinally. In adolescent, in vivo multi-electrode array recordings evaluated lamina-specific DH responses to mechanical and electrical stimulation, including frequency-dependent facilitation (wind-up). Immunohistochemistry quantified parvalbumin (PV), protein kinase C gamma (PKCγ), and somatostatin (SOM) expression. Preadolescent morphine exposure (PME) induced transient mechanical hypersensitivity in males immediately after treatment, whereas both sexes exhibited reduced sensitivity to mechanical stimulation at P40. PME was associated with enhanced mechanical evoked activity in the intermediate DH, alongside an absence of wind-up in this region. In the deep DH, wind-up was reduced in males but enhanced in females. PV expression was increased in both sexes and positively correlated with paw withdrawal thresholds. In contrast, PKCγ expression was reduced in males and SOM expression was reduced in females. These findings demonstrate that PME is associated with alterations in spinal nociceptive processing that is lamina and sex dependent. Changes in inhibitory and excitatory interneuron markers suggest a shift in DH circuit organisation which may contribute to altered sensory processing following early life opioid exposure. PERSPECTIVE: Preadolescent opioid exposure is associated with lasting changes in spinal nociceptive processing. These findings suggest that opioid use during critical developmental periods may influence long-term pain sensitivity, highlighting the importance of understanding how early-life analgesic strategies shape future sensory function.