The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity.
We used a mouse with deletion of exons 4, 5, and 6 of the SCN11A (sodium channel, voltage-gated, type XI, alpha) gene that encodes the voltage-gated sodium channel Na(v)1.9 to assess its contribution to pain. Na(v)1.9 is present in nociceptor sensory neurons that express TRPV1, bradykinin B2, and purinergic P2X3 receptors. In Na(v)1.9-/- mice, the non-inactivating persistent tetrodotoxin-resistant sodium TTXr-Per current is absent, whereas TTXr-Slow is unchanged. TTXs currents are unaffected by the mutation of Na(v)1.9. Pain hypersensitivity elicited by intraplantar administration of prostaglandin E2, bradykinin, interleukin-1beta, capsaicin, and P2X3 and P2Y receptor agonists, but not NGF, is either reduced or absent in Na(v)1.9-/- mice, whereas basal thermal and mechanical pain sensitivity is unchanged. Thermal, but not mechanical, hypersensitivity produced by peripheral inflammation (intraplanatar complete Freund's adjuvant) is substantially diminished in the null allele mutant mice, whereas hypersensitivity in two neuropathic pain models is unchanged in the Na(v)1.9-/- mice. Na(v)1.9 is, we conclude, an effector of the hypersensitivity produced by multiple inflammatory mediators on nociceptor peripheral terminals and therefore plays a key role in mediating peripheral sensitization.
Amaya
Fumimasa
F
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Wang
Haibin
H
Costigan
Michael
M
Allchorne
Andrew J
AJ
Hatcher
Jon P
JP
Egerton
Julie
J
Stean
Tania
T
Morisset
Valerie
V
Grose
David
D
Gunthorpe
Martin J
MJ
Chessell
Iain P
IP
Tate
Simon
S
Green
Paula J
PJ
Woolf
Clifford J
CJ
D000818:Animals; D005260:Female; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000378:metabolism; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D010146:Pain / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D010525:Peripheral Nerves / Q000378:metabolism*; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics
D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C491885:Scn11a protein, mouse; D015222:Sodium Channels