Nociceptors are interleukin-1beta sensors.
A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E(2), bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1beta (IL-1beta), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1beta acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1beta sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.
Binshtok
Alexander M
AM
Neural Plasticity Research Group, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Wang
Haibin
H
Zimmermann
Katharina
K
Amaya
Fumimasa
F
Vardeh
Daniel
D
Shi
Lin
L
Brenner
Gary J
GJ
Ji
Ru-Rong
RR
Bean
Bruce P
BP
Woolf
Clifford J
CJ
Samad
Tarek A
TA
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D064531:Peripherins; D010812:Physical Stimulation / Q000379:methods; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D053583:Interleukin-1beta; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D064531:Peripherins; D011725:Pyridines; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580