Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids.
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.
Wallace
Victoria C J
VC
Centre for Neuroscience Research, Division of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
Cottrell
David F
DF
Brophy
Peter J
PJ
Fleetwood-Walker
Susan M
SM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020422:Mononeuropathies / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D009475:Neurons, Afferent / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009478:Neuropeptide Y / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists; D012018:Reflex / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015222:Sodium Channels / Q000378:metabolism
D002186:Cannabinoids; D018691:Excitatory Amino Acid Antagonists; D008244:Lysophosphatidylcholines; D009478:Neuropeptide Y; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D015222:Sodium Channels