Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas.
OBJECTIVE
Although axons within neuromas have been shown to produce inappropriate spontaneous ectopic discharges, the molecular basis for pain in patients with neuromas is still not fully understood. Because sodium channels are known to play critical roles in neuronal electrogenesis and hyperexcitability, we examined the expression of all the neuronal voltage-gated sodium channels (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) within human painful neuromas. We also examined the expression of two mitogen-activated protein (MAP) kinases, activated p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are known to contribute to chronic pain, within these human neuromas.


METHODS
We used immunocytochemical methods with specific antibodies to sodium channels Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9, and to activated MAP kinases p38 and ERK1/2 to study by confocal microscopy control and painful neuroma tissue from five patients with well-documented pain.


RESULTS
We demonstrate upregulation of sodium channel Nav1.3, as well as Nav1.7 and Nav1.8, in blind-ending axons within human painful neuromas. We also demonstrate upregulation of activated p38 and ERK1/2 MAP kinases in axons within these neuromas.


CONCLUSIONS
These results demonstrate that multiple sodium channel isoforms (Nav1.3, Nav1.7, and Nav1.8), as well as activated p38 and ERK1/2 MAP kinases, are expressed in painful human neuromas, indicating that these molecules merit study as possible therapeutic targets for the treatment of pain associated with traumatic neuromas.
Black
Joel A
JA
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, USA. joel.black@yale.edu
Nikolajsen
Lone
L
Kroner
Karsten
K
Jensen
Troels S
TS
Waxman
Stephen G
SG
D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D009463:Neuroma / Q000201:enzymology / Q000378:metabolism* / Q000601:surgery; D010146:Pain / Q000201:enzymology / Q000378:metabolism* / Q000601:surgery; D020033:Protein Isoforms / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D015222:Sodium Channels / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D020033:Protein Isoforms; D015222:Sodium Channels; D020928:Mitogen-Activated Protein Kinases