Focal Lysolecithin-Induced Demyelination of Peripheral Afferents Results in Neuropathic Pain Behavior That Is Attenuated by Cannabinoids

Abstract

Demyelinating diseases can be associated with painful sensory phenomena such as tactile allodynia and hyperalgesia. To study the mechanisms underlying demyelination-induced pain, we have characterized a novel model of demyelination of the sciatic or saphenous nerve. Topical lysolecithin application causes focal demyelination of afferent nerve A-fibers without axonal loss, as assessed either by electron and light microscopy or by immunohistochemical analysis of dorsal root ganglia (DRG) for a neuronal injury marker, activating transcription factor 3. Focal demyelination is accompanied by spontaneous action potentials in afferents and increased expression of neuropeptide Y and Na(v)1.3 sodium channels specifically in DRG neurons that coexpress a specific marker of myelinated afferents. In contrast, expression of tetrodotoxin-resistant, Na(v)1.8 sodium channels is specifically decreased in the same subgroup of DRG cells. Central sensitization of somatosensory processing is also induced, with increased behavioral reflex responsiveness to thermal and mechanical stimuli. These changes are reversed by intrathecal administration of an NMDA receptor antagonist or cannabinoid (CB) receptor agonist, but not by a mu-opioid receptor agonist. Recovery of behavioral reflexes occurred approximately 3 weeks after lysolecithin treatment. This is the first time that demyelination of afferent A-fibers has been shown to specifically induce neuropathic pain and indicates that axonal damage is not a prerequisite for development of the pain state. The profile of phenotypic changes in DRG is distinct from other pain models and displays a sensitivity to NMDA and CB receptor agents that may be exploitable therapeutically.

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…In particular, the myelin degradation of A␤ afferents promotes susceptibility of their axonal plasma membrane to pronociceptive stimuli, leading to ectopic depolarization and mechanical allodynia (Kobayashi et al, 2008). Accordingly, neuropathic pain behaviors occurred after experimental demyelination of peripheral or central neurons (Wallace et al, 2003;Inoue et al, 2004;Moalem-Taylor et al, 2007;Zhu et al, 2012) and in mutant mice with aberrant myelination or loss of myelin (Gillespie et al, 2000;Chen et al, 2006). Moreover, neuropathic pain accompanies many demyelinating human diseases, such as Guillain-Barré syndrome, CharcotMarie-Tooth type I disease, and multiple sclerosis (Ueda, 2008).…”

“…We speculated that a disruption of myelin sheath integrity of peripheral nerves might be involved, because previous work demonstrated that (1) the myelin sheath is highly susceptible to degeneration caused by H 2 O 2 (Konat and Wiggins, 1985;Richter-Landsberg and Vollgraf, 1998;Laszkiewicz et al, 1999;Mronga et al, 2004;Perfeito et al, 2007), (2) the myelin sheath is disrupted and the proximal nerve stump seals off after peripheral nerve injury (Inoue et al, 2004;Devor, 2006a;Nagai et al, 2010), and (3) the dysmyelination of peripheral nerves induced by nerve injury or by delivery of bioactive lipids, such as lysophosphatidic acid, is accompanied by spontaneous action potentials in primary afferent nerves and sensitization of sensory processing, thereby contributing to neuropathic pain hypersensitivity (Devor et al, 1989;Wallace et al, 2003;Devor, 2006b;Ueda, 2008;Zhu et al, 2012). To monitor the time course of injury-induced dysmyelination of peripheral nerves in the SNI model, we first analyzed the protein levels of MPZ, the main peripheral myelin protein, in C57BL/6 mice during 21 d after SNI.…”

Cysteine-Rich Protein 2, a Novel Downstream Effector of cGMP/cGMP-Dependent Protein Kinase I-Mediated Persistent Inflammatory Pain

“…The majority (82.9%) of CRP2 mRNA-positive neurons were positive for peripherin (Fig. 4 D-F ), which labels the small-diameter, unmyelinated C-fiber DRG cell population (Wallace et al, 2003). Only a small portion (7.8%) of CRP2 mRNA-positive neurons expressed NF200 (clone N52), a marker of large-diameter, myelinated DRG neurons (Fig.…”

Early events in node of Ranvier formation during myelination and remyelination in the PNS

“…Alternatively, whereas demyelination in the CNS results in upregulation of Nav1.2, demyelination in the PNS might result in upregulation of Nav1.8 or another Nav channel. For example, Wallace et al (2003) showed that lysolecithinmediated demyelination upregulates Nav1.3 channel expression in DRG neurons. It is not known whether this Nav1.3 is transported into axons and/or localizes to specific membrane domains (e.g.…”