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The Journal of Neuroscience, August 31, 2005, 25(35):7986-7992; doi:10.1523/JNEUROSCI.2393-05.2005

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Behavioral/Systems/Cognitive
Bradykinin Produces Pain Hypersensitivity by Potentiating Spinal Cord Glutamatergic Synaptic Transmission

Haibin Wang,^1 * Tatsuro Kohno,^1 * Fumimasa Amaya,¹ Gary J. Brenner,¹ Nobuko Ito,¹ Andrew Allchorne,¹ Ru-Rong Ji,² and Clifford J. Woolf¹

¹Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, and ²Pain Research Center, Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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.

Key words: bradykinin; spinal cord; pain; synaptic transmission; glutamate; neuromodulator

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Received June 10, 2005; revised July 18, 2005; accepted July 18, 2005.

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