Inflammatory Mediators Sensitize Acutely Axotomized Nerve Fibers to Mechanical Stimulation in the Rat

Abstract

Many axotomized myelinated as well as unmyelinated cutaneous nerve fibers are sensitive to mechanical stimuli applied to the cut nerve end within a few hours after nerve lesion. Here we investigated the influence of inflammatory mediators on this ectopic mechanosensitivity after cutting and ligating the sural nerve in anesthetized rats. Neural activity was recorded from single axons in filaments teased from the sural or sciatic nerve proximally to the lesion site 2-33 hr after axotomy. Using calibrated von Frey hairs (1.0-128.5 mN), 30 sec trains of phasic stimuli were applied to the cut nerve end immediately before and after local application of a mixture of inflammatory mediators [inflammatory soup (IS), consisting of bradykinin, 5-HT, prostaglandin E2, histamine (all 10 microM), and K+ 7 mM, pH 7.0] for 2 min. Before as well as after IS application, von Frey thresholds were significantly lower in myelinated (A) fibers than in unmyelinated (C) fibers. IS application enhanced the ectopic mechanical excitability, as expressed in reduced von Frey thresholds and increased response magnitudes, of most severed mechanosensitive C fibers (77%) and some mechanosensitive A fibers (46%). The sensitization lasted for 10-40 min after a 2 min IS application. Additionally, among axotomized nerve fibers unresponsive to probing of the nerve lesion site before IS application, 1 of 63 (1.6%) A and 3 of 106 (2.8%) C fibers became mechanosensitive immediately after IS application. The results indicate that after axotomy, inflammatory processes augment touch-evoked ectopic activity in lesioned sensory nerve fibers. Because many affected afferents are presumably of nociceptive function, their enhanced neural barrage may contribute to neuropathic pain states.

Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways

“…At present, the strongest evidence of a robust peripheral sensitization to mechanical stimuli comes from studies of the nociceptive innervation of joints (6), the viscera (7), the dura (5), and from nerve endings in neuromas (8,9). In each case, chemical stimulation leads to a decrease in mechanical threshold and increased suprathreshold firing.…”

“…Although the prevalence of peripheral mechanical sensitization has been questioned in cutaneous C fiber nociceptors (3,4), there are extensive data showing peripheral sensitization to mechanical stimuli of nociceptors innervating a variety of deep tissues, including the meninges (5), joints (6), viscera (7), and injured axons terminating in neuromas (8,9). Therefore, increased mechanosensitivity could play a major role in the pathophysiology of headache, arthritis, visceral pain, and neuropathic pain.…”

Prostaglandin E2 and 6‐keto‐prostaglandin F1α production is elevated following traumatic injury to sciatic nerve†

“…It is well established that PGE 2 and PGI 2 sensitize peripheral nerve fibers following traumatic injury (Michaelis et al, 1998;Smith et al, 1998;Baba et al, 2001;Omana-Zapata and Bley, 2001). However, the physiologic effects of prostanoids on cells intrinsic to injured peripheral nerve remain to be determined.…”

Activity-Dependent Modulation of Axonal Excitability in Unmyelinated Peripheral Rat Nerve Fibers by the 5-HT(3) Serotonin Receptor

“…2). An example of a functional consequence is the finding that serotonin sensitizes acutely axotomized nerve fibers to mechanical stimuli (Michaelis et al 1998). Effects of serotonin have been also observed on motor axons.…”

“…In the present study, we have tested whether the recovery cycle in C-fibers is modulated by the subtype 3 of the 5-hydroxytryptamine [5-HT(3)] serotonin receptor. 5-HT(3) is an important component in the group of inflammatory mediators (Dray 1995;Moalem and Tracey 2006) and contributes to peripheral sensitization and hyperalgesia in inflammation and nerve injury (Michaelis et al 1998;Sommer 2004). After genetic or pharmacological disruption of the 5-HT(3) receptor, persistent, but not acute nociception induced by tissue injury, is significantly reduced (Zeitz et al 2002).…”