Peripheral Nerve Pathology Following Sciatic Cryoneurolysis: Relationship to Neuropathic Behaviors in the Rat

Abstract

Sciatic cryoneurolysis (SCN) is an experimental rat mononeuropathy model that produces neuropathic behavioral sequelae distinct from other neuropathy models. Following SCN, there is limited autotomy peaking in severity and incidence at 7-14 days and delayed but sustained allodynia appearing at about 21 days, with no evidence of thermal hyperalgesia. This study quantified peripheral nerve pathology at weekly intervals following SCN to determine the relationship of nerve degeneration and regeneration to the resulting abnormal behaviors. Fiber histograms based on axon diameter and grid morphometry were used to quantify the pathologic state of nerve fibers, activated phagocytic cells, vessels, and edema at the lesion site. Approximately 90% of the axons demonstrated Wallerianlike degeneration by 3 days post-SCN. At 14 days, small diameter axons significantly increased in number from earlier times following SCN (P < 0.05) but were not significantly different from normal values. At 21 days, the number of small diameter axons was significantly increased over both 14 days (P < 0.05) and normal values (P < 0.05). At 28 days, intermediate diameter axons significantly increased in number with respect to all earlier time periods (P < 0.05). These increases in regenerating fibers overlapped with the development of peak autotomy at 7-14 days and the onset of allodynia after 21 days. Autotomy scores at 7 days positively correlated with grid morphometry data of regenerating axons (p = 0.7) and activated macrophages and Schwann cells (p = 0.8) and inversely correlated with edema (p= -0.8) using Spearman's rank correlation analysis. These data suggest a macrophage and Schwann cell involvement in the sensitization of first- and second-order neurons to afferent input which leads to neuropathic behaviors. These results are discussed in the context of a hypothesis for the generation of differential neuropathic behaviors associated with the pathological events of degeneration and regeneration following the chronic constriction injury model of neuropathic pain and SNC.