Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission.
Bradykinin, an inflammatory mediator, sensitizes nociceptor peripheral terminals reducing pain threshold. We now show that the B2 kinin receptor is expressed in rat dorsal horn neurons and that bradykinin, a B2-specific agonist, augments AMPA- and NMDA-induced, and primary afferent-evoked EPSCs, and increases the frequency and amplitude of miniature EPSCs in superficial dorsal horn neurons in vitro. Administration of bradykinin to the spinal cord in vivo produces, moreover, an NMDA-dependent hyperalgesia. We also demonstrate that nociceptive inputs result in the production of bradykinin in the spinal cord and that an intrathecal B2-selective antagonist suppresses behavioral manifestations of central sensitization, an activity-dependent increase in glutamatergic synaptic efficacy. Primary afferent-evoked central sensitization is, in addition, reduced in B2 receptor knock-out mice. We conclude that bradykinin is released in the spinal cord in response to nociceptor inputs and acts as a synaptic neuromodulator, potentiating glutamatergic synaptic transmission to produce pain hypersensitivity.
Wang
Haibin
H
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Kohno
Tatsuro
T
Amaya
Fumimasa
F
Brenner
Gary J
GJ
Ito
Nobuko
N
Allchorne
Andrew
A
Ji
Ru-Rong
RR
Woolf
Clifford J
CJ
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology* / Q000502:physiology; D004357:Drug Synergism; D018698:Glutamic Acid / Q000502:physiology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology* / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000819:agonists / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
D043782:Receptor, Bradykinin B2; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001920:Bradykinin