Abstract
BackgroundThe term ‘irritable nociceptor’ was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels.Methods In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham‐operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn.ResultsIn neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind‐up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical‐, dynamic brush‐ and cold‐evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat‐evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action.ConclusionsWe provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine through a peripheral mechanism exhibits modality‐selective inhibitory effects on sensory neuronal processing.SignificanceThe inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism‐based rationale for bench‐to‐bedside translation when screening novel drugs.
Highlights
Neuropathic pain remains poorly treated for the majority of patients
The first was largely characterized by sensory loss and ongoing pain which was insensitive to local lidocaine infusion, whereas in the second group severe allodynia was the most prominent sensory disturbance, but in these cases local lidocaine alleviated ongoing pain (Rowbotham & Fields, 1989). The latter group is more commonly described as the irritable nociceptor phenotype and the former as non‐irritable/deafferentation‐type pain, the features of both sensory phenotypes can be present within the same patient (Fields, Rowbotham, & Baron, 1998)
This study for the first time reports that elevated spontaneous thalamic firing in the spinal nerve ligated (SNL) model is dependent on ongoing peripheral activity
Summary
Neuropathic pain remains poorly treated for the majority of patients. Emerging evidence, largely from post hoc analysis of clinical trial data, supports that sensory profiling of neuropathic patients could improve patient outcomes by targeting specific underlying mechanisms (Bouhassira & Attal, 2016; Simpson et al, 2010; Yarnitsky, Granot, Nahman‐Averbuch, Khamaisi, & Granovsky, 2012). We aimed to back‐translate two clinical observations based on sensory profiling providing preliminary evidence that patients with the irritable nociceptor phenotype may benefit from the anticonvulsant oxcarbazepine (Demant et al, 2014) and a topical lidocaine patch against certain secondary pain measures (Demant et al, 2015). To this end, we examined the effects of lidocaine and oxcarbazepine in the spinal nerve ligation (SNL) model, which involves selective ligation and injury of the L5 and L6 spinal nerves, and preservation of L4 afferents. These characterizations represent an objective and quantifiable neural substrate of sensory function that overcomes many of the limitations of reflexive endpoints
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