Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity.
Bradykinin potentiates synaptic glutamate release and action in the spinal cord via presynaptic and postsynaptic B(2) receptors, contributing thereby to activity-dependent central sensitization and pain hypersensitivity (Wang et al., 2005). We have now examined the signaling pathways that are responsible for the postsynaptic modulatory actions of bradykinin on glutamatergic action and transmission in superficial dorsal horn neurons. B(2) receptors are coexpressed in dorsal horn neurons with protein kinase A (PKA) and the delta isoform of protein kinase C (PKC), and we find that the augmentation by bradykinin of AMPA and NMDA receptor-mediated currents in lamina II neurons requires coactivation of both PKC and PKA. The activation of PKA is downstream of COX1 (cyclooxygenase-1). Extracellular signal-regulated kinase (ERK) activation is involved after the PKC and PKA coactivation, and intrathecal administration of bradykinin induces a thermal hyperalgesia in vivo, which is reduced by inhibition of ERK, PKA, and PKC. We conclude that bradykinin, by activating multiple kinases in dorsal horn neurons, potentiates glutamatergic synaptic transmission to produce pain hypersensitivity.
Kohno
Tatsuro
T
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Wang
Haibin
H
Amaya
Fumimasa
F
Brenner
Gary J
GJ
Cheng
Jen-Kun
JK
Ji
Ru-Rong
RR
Woolf
Clifford J
CJ
D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology*; D066298:In Vitro Techniques; D010146:Pain / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011494:Protein Kinases; D001920:Bradykinin