Bilateral sensitization after unilateral trauma is sex- and age-dependent in mice

As a posttraumatic reaction after distal bone fracture, hypersensitivity to mechanical stimuli develops, spinal receptive fields enlarge mostly ipsilateral to the injury and the adrenergic receptor composition alters in peripheral and central nervous tissue. Many of these changes subside during fracture healing. In humans, CRPS can develop after distal bone fracture with long-lasting pain in the affected limb and, sometimes, contralaterally. This study shows contralateral effects after distal bone fracture in mice. Contralateral hypersensitivity develops in aging groups, in females earlier than in males. Aging males display contralateral spread of spinal changes to the neuronal network and activity. Field sizes can massively enlarge in a glove- or stocking-like distribution and cluster in the cord as early as in the posttraumatic phase. In these cases, clusters of fields shrink on the ipsilateral side long after trauma. Spinal neurons with abnormally large (in the posttraumatic phase) and later small (in the chronic phase) receptive fields respond strongly to pressure stimuli. Thus, hypersensitivity to pressure, occurring in many CRPS-like cases, might reflect a spinal status of altered connectivity. Further, alpha-adrenergic receptors are bilaterally differentially regulated in the spinal cord and locus coeruleus after bone trauma in aging male mice, potentially contributing to neuronal hyperexcitability in pain pathways during aging. PERSPECTIVE: Contralateral spread of hypersensitivity can occur after distal bone fracture in mice, primarily of female sex and/ or older age. Spinal network alterations and spinal and supraspinal adrenoceptor dysregulation also occurs in aging male mice.