The Persistent Sciatic Inflammatory Neuropathy (SIN) Rat Model of Neuropathic Pain Does Not Involve Small-Fiber Axon Damage

Abstract

Most neuropathic pain conditions are caused by damage to peripheral nociceptive neurons known as “small-fibers.” Examination of punch skin biopsies immunolabeled with pan-axonal markers has identified degeneration of distal nociceptive axons as a pathological hallmark of most neuralgias including numerous polyneuropathies, postherpetic neuralgia, and complex regional pain syndrome. Similar axonopathy is present in several rodent models of neuralgia (chronic constriction injury and spared nerve injury). Here we have measured the density of distal cutaneous small-fiber axons in rats with persistent mechanical allodynia caused by the sciatic inflammatory neuropathy (SIN), a model of painful neuritis. We have evaluated whether perineural immune activation sufficient to cause evoked-pain behaviors is also associated with loss of distal epidermal innervation.SIN was created in adult male Sprague-Dawley rats by perineural zymosan administration using established methods. Unoperated rats provided controls. Two weeks of sensory testing established the presence of static mechanical allodynia. Full-thickness punches were then collected from ipsilesional sural-innervated plantar hindpaw skin. These were immunolabeled against PGP9.5 using standard methods, and the density of epidermal neurites quantitated microscopically by a single examiner who was unaware of rats' experimental group. Neurite densities were similar in SIN and control samples (P = 0.96), suggesting that mechanical allodynia can occur from inflammation near a nerve, without distal small-fiber degeneration.