Reduced Nerve Injury-Induced Neuropathic Pain in Kinin B₁Receptor Knock-Out Mice

Abstract

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 B 1 receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B 1 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 B 1 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.

Antinociceptive Pharmacology ofN-[[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide, Fumarate (LF22-0542), a Novel Nonpeptidic Bradykinin B1Receptor Antagonist

“…Recent findings suggest the requirement for the B 1 receptor in neuropathic pain resulting from injuries to peripheral nerves (Ferreira et al, 2005). The data with LF22-0542 support a significant role of the B 1 receptor in mediating nerve injury-induced thermal hypersensitivity but not tactile hypersensitivity.…”

“…However, B 1 KO animals did not develop thermal hypersensitivity but nevertheless showed SNL-induced tactile hypersensitivity that did not differ from the WT animals. Pesquero and colleagues have reported that B 1 KO mice did not develop either tactile or thermal hypersensitivity after nerve injury (Ferreira et al, 2005). In those studies the authors used mice from the same source as in the present studies but used a different model nerve injury (i.e., partial ligation of the sciatic nerve).…”

Neuropathic Pain-Like Behavior after Brachial Plexus Avulsion in Mice: The Relevance of Kinin B1and B2Receptors

“…In addition, the systemic administration of B 1 R antagonist des-Arg 9 -Leu 8 -BK was able to reduce thermal and mechanical hypernociception induced by sciatic nerve constriction in rats (Levy and Zochodne, 2000;Yamaguchi-Sase et al, 2003). Interestingly, the gene deletion of B 1 R practically abolished the hypernociception produced by sciatic nerve injury in mice (Ferreira et al, 2005).…”

Inflammatory mediators of neuropathic pain

“…Experimental intraplantar injections of B1 or B2 receptor agonists increase response to pain 12 , while antagonists injection inhibits hyperalgesia in NP models 13 . Decreased hyperalgesia secondary to nervous injury obtained by deleting the gene responsible for B1 receptors in mice confirms the important role of bradykinin as central inflammatory mediator in NP 14,15 .…”