Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice.
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.
Ferreira
Juliano
J
Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, 88015-420 Florianópolis, Brazil. ferreiraj99@bol.com.br
Beirith
Alessandra
A
Mori
Marcelo A S
MA
Araújo
Ronaldo C
RC
Bader
Michael
M
Pesquero
João B
JB
Calixto
João B
JB
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D065169:Bradykinin B1 Receptor Antagonists; D005260:Female; D007839:Functional Laterality; D015870:Gene Expression / Q000502:physiology; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology; D009437:Neuralgia / Q000209:etiology* / Q000628:therapy; D010147:Pain Measurement / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020426:Sciatic Neuropathy / Q000150:complications*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012881:Skin Temperature / Q000235:genetics; D013997:Time Factors
D065169:Bradykinin B1 Receptor Antagonists; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; C024626:bradykinin, des-Arg(9)-; C051090:bradykinin, Leu(8)-des-Arg(9)-; D001920:Bradykinin
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