Brief, low frequency stimulation of rat peripheral C-fibres evokes prolonged microglial-induced central sensitization in adults but not in neonates

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Abstract
Act nature of the afferent input that triggers the activation of microglia and other glial cells within the CNS, remains unclear. Here intense but non-damaging, electrical stimulation of intact adult rat C-fibres for 5 min at 10 Hz induced central sensitization characterized by significant decreases in mechanical withdrawal thresholds 3, 24 and 48 h later. This maintained (>3 h) hypersensitivity was not observed following topical skin application of capsaicin. C-fibre evoked sensitization was accompanied by significant microglial activation, shown by increased Iba-1 immunoreactivity throughout the dorsal horn at 24 and 48 h and significant upregulation of markers of microglial activation: IL-6 and Mcp-1 at 3 h and Mmp3, CSF-1 and CD163 at 24 and 48 h. C-fibre stimulation caused no nerve damage at ultrastructural and molecular levels. Lower intensity stimulation that did not activate C-fibres or sham stimulation did not increase Iba-1 immunoreactivity or induce behavioural sensitivity. Pre-treatment with minocycline (40 mg/kg, i.p.) prevented the C-fibre evoked sensitization and microglial activation. Identical C-fibre stimulation in 10-day old rat pups failed to activate microglia or change behaviour. These results demonstrate that a brief period of low frequency C-fibre stimulation, in the absence of nerve damage, is sufficient to activate microglia resulting in behavioural hyperalgesia....