Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats

Abstract

After mechanical injury of a peripheral nerve some axotomized afferent neurons develop spontaneous activity, which is thought to trigger abnormal pain behavior in rats and neuropathic pain in humans. Here, we analysed the ectopic activity in axotomized afferent fibers recorded from the L5 dorsal root in different time periods after L5 spinal nerve lesion and the effects of sympathectomy on it. The following results were obtained: (1) Up to 6 hours after spinal nerve transection there was almost no spontaneous activity in axotomized afferents, except short-lasting injury discharges at the time of transection; (2) Three to 8 days following spinal nerve lesion, the rate of spontaneous activity was 7.3+/-7.7 imp/s (mean+/-SD, median 5.0 imp/s, n=204); 41.6% of the spontaneously active afferent neurons exhibited a bursting pattern with interspike intervals of 32.4+/-18.3 ms; (3) Twenty to 53 days after nerve lesion the rate of spontaneous activity had decreased significantly to 3.4+/-4.3 imp/s (median 2.6 imp/s, n=120). The frequency of bursting and non-bursting neurons remained roughly the same; (4) In sympathectomized rats, 15-45 days following spinal nerve lesion, the mean discharge rate was 3.8+/-4.3 imp/s (median 2. 3 imp/s, n=255). However, the percentage of bursting neurons and the intraburst frequency decreased significantly; (5) Spontaneous activity occurred in afferent A-fibers but not in afferent C-fibers. These results suggest that ectopic activity in axotomized afferent neurons develops within the first days after L5 spinal nerve lesion, decreases with time and is only marginally dependent on the sympathetic innervation. There was a positive correlation between this ectopic activity and the allodynia-like behavior in spinal nerve-lesioned rats.

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

“…We selected medium-sized neurons since they include nociceptors, and because they constitute a physiologically relevant cellular population that develops increased excitability after nerve injury [58,80]. Several studies have indicated that this neuronal population exhibits the most significant phenotypic changes after nerve injury [11,23,53,55,56,63,80,98]. Our observations on iberiotoxin-sensitive current in small neurons demonstrates that injury-related effects on primary afferent neurons are not unique to the medium size group.…”

“…We therefore chose to focus on this representative population. Several studies have indicated that medium sized somata with axons of Aδ-fiber caliber exhibit significant phenotypic changes after nerve injury, and may be an important generator of ectopic discharges [11,23,53,55,56,63,98]. In addition, a previous study from our lab showed that Aδ fibers exhibited the most pronounced electrophysiological changes after SNL, and in particular increased AP duration, decreased AHP amplitude and duration, and increased repetitive firing during sustained depolarization, manifestations that may explain increased neuronal excitability and hyperalgesia in neuropathic pain states [80].…”

Spinal Fbxo3-Dependent Fbxl2 Ubiquitination of Active Zone Protein RIM1α Mediates Neuropathic Allodynia through CaV2.2 Activation

“…In Fbxl2-KO mice, RIM1 has a longer half-life, and it has the ability to significantly reduce ubiquitination in association with an enhanced frequency of miniature EPSCs (mEPSCs) in the CA3-CA1 synapse (Yao et al, 2007). Recently, studies have revealed that Fbxo3, another E3-ubiquitin ligase subunit, potently stimulates cytokine secretion by destabilizing Fbxl2 (Chen et al, 2013;. Together, these studies link the Fbxo3/Fbxl2 cascade to RIM1␣ unubiquitination and activation.…”

An Approach to Identify Nerve Injury-Evoked Changes that Contribute to the Development or Protect Against the Development of Sustained Neuropathic Pain

“…Peripheral nerve injury-evoked changes in impulse generation include the appearance of ectopic afferent impulses and the modification of the stimuli-evoked impulses. Following sciatic nerve injury (constriction or cutting), ectopic discharges (firing of action potentials) from the injured site (Tal and Eliav, 1996;Wall and Gutnick, 1974a;Wall and Gutnick, 1974b;Wall and Devor, 1983) and the dorsal root ganglia (Amir et al, 2002;Liu et al, 2000a;Liu et al, 1999;Liu et al, 2000b) correlate with the development of neuropathic pain. The frequency of ectopic discharges shows a transient increase within the first 24 hrs following spinal nerve ligation (Sun et al, 2005).…”