Activation of the regeneration-associated gene STAT3 and functional changes in intact nociceptors after peripheral nerve damage in mice.
In the context of neuropathic pain, the contribution of regeneration to the development of positive symptoms is not completely understood. Several efforts have been done to described changes in axotomized neurons, however, there is scarce data on changes occurring in intact neurons, despite experimental evidence of functional changes. To address this issue, we analyzed by immunohistochemistry the presence of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), an accepted marker of regeneration, within DRGs where axotomized neurons were retrogradely labeled following peripheral nerve injury. Likewise, we have characterized abnormal electrophysiological properties in intact fibers after partial nerve injury.We showed that induction of pSTAT3 in sensory neurons was similar after partial or total transection of the sciatic nerve and to the same extent within axotomized and non-axotomized neurons. We also examined pSTAT3 presence on non-peptidergic and peptidergic nociceptors. Whereas the percentage of neurons marked by IB4 decrease after injury, the proportion of CGRP neurons did not change, but its expression switched from small- to large-diameter neurons. Besides, the percentage of CGRP+ neurons expressing pSTAT3 increased significantly 2.5-folds after axotomy, preferentially in neurons with large diameters. Electrophysiological recordings showed that after nerve damage, most of the neurons with ectopic spontaneous activity (39/46) were non-axotomized C-fibers with functional receptive fields in the skin far beyond the site of damage.Neuronal regeneration after nerve injury, likely triggered from the site of injury, may explain the abnormal functional properties gained by intact neurons, reinforcing their role in neuropathic pain.