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The Journal of Neuroscience, March 2, 2005, 25(9):2405-2412; doi:10.1523/JNEUROSCI.2466-04.2005

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Behavioral/Systems/Cognitive
Reduced Nerve Injury-Induced Neuropathic Pain in Kinin B₁ Receptor Knock-Out Mice

Juliano Ferreira,¹ Alessandra Beirith,¹ Marcelo A. S. Mori,² Ronaldo C. Araújo,³ Michael Bader,⁴ João B. Pesquero,² and João B. Calixto¹

¹Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, 88015-420 Florianópolis, Brazil, ²Department of Biophysics, Escola Paulista de Medicina, 04023-062 São Paulo, Brazil, ³Universidade de Mogi das Cruzes, 08780-91 Mogi das Cruzes, Brazil, and ⁴Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin-Buch, Germany

Injury to peripheral nerves often results in a persistent neuropathic pain condition that is characterized by spontaneous pain, allodynia, and hyperalgesia. Nerve injury is accompanied by a local inflammatory reaction in which nerve-associated and immune cells release several pronociceptive mediators. Kinin B₁ receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B₁ receptors mediate chronic inflammatory painful processes, we studied their participation in neuropathic pain using receptor gene-deleted mice. In the absence of neuropathy, we found no difference in the paw-withdrawal responses to thermal or mechanical stimulation between B₁ receptor knock-out mice and 129/J wild-type mice. Partial ligation of the sciatic nerve in the wild-type mouse produced a profound and long-lasting decrease in thermal and mechanical thresholds in the paw ipsilateral to nerve lesion. Threshold changed neither in the sham-operated animals nor in the paw contralateral to lesion. Ablation of the gene for the B₁ receptor resulted in a significant reduction in early stages of mechanical allodynia and thermal hyperalgesia. Furthermore, systemic treatment with the B₁ selective receptor antagonist des-Arg⁹-[Leu⁸]-bradykinin reduced the established mechanical allodynia observed 7-28 d after nerve lesion in wild-type mice. Partial sciatic nerve ligation induced an upregulation in B₁ receptor mRNA in ipsilateral paw, sciatic nerve, and spinal cord of wild-type mice. Together, kinin B₁ receptor activation seems to be essential to neuropathic pain development, suggesting that an oral-selective B₁ receptor antagonist might have therapeutic potential in the management of chronic pain.

Key words: neuropathic pain; allodynia; hyperalgesia; B₁ receptor; kinin; bradykinin

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Received June 22, 2004; revised January 12, 2005; accepted January 14, 2005.

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