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The Journal of Neuroscience, April 23, 2008, 28(17):4533-4540; doi:10.1523/JNEUROSCI.5349-07.2008

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Cellular/Molecular
Bradykinin Enhances AMPA and NMDA Receptor Activity in Spinal Cord Dorsal Horn Neurons by Activating Multiple Kinases to Produce Pain Hypersensitivity

Tatsuro Kohno,^1,2 * Haibin Wang,^1 * Fumimasa Amaya,¹ Gary J. Brenner,¹ Jen-Kun Cheng,³ Ru-Rong Ji,³ and Clifford J. Woolf¹

¹Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, ²Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan, and ³Pain Research Center, Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Clifford J. Woolf, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129. Email: cwoolf{at}partners.org

Bradykinin potentiates synaptic glutamate release and action in the spinal cord via presynaptic and postsynaptic B₂ 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. B₂ receptors are coexpressed in dorsal horn neurons with protein kinase A (PKA) and the 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.

Key words: bradykinin; spinal cord; pain; glutamate; neuromodulator; signal transduction

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Received July 30, 2007; revised Feb. 28, 2008; accepted March 19, 2008.

Correspondence should be addressed to Dr. Clifford J. Woolf, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129. Email: cwoolf{at}partners.org

This article has been cited by other articles:

				H. Cao, Y.-J. Gao, W.-H. Ren, T.-T. Li, K.-Z. Duan, Y.-H. Cui, X.-H. Cao, Z.-Q. Zhao, R.-R. Ji, and Y.-Q. Zhang Activation of Extracellular Signal-Regulated Kinase in the Anterior Cingulate Cortex Contributes to the Induction and Expression of Affective Pain J. Neurosci., March 11, 2009; 29(10): 3307 - 3321. [Abstract] [Full Text] [PDF]

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