Tibial post fracture pain is reduced in kinin receptors deficient mice and blunted by kinin receptor antagonists

J Transl Med. 2019 Oct 22;17(1):346. doi: 10.1186/s12967-019-2095-9.


Background: Tibial fracture is associated with inflammatory reaction leading to severe pain syndrome. Bradykinin receptor activation is involved in inflammatory reactions, but has never been investigated in fracture pain.

Methods: This study aims at defining the role of B1 and B2-kinin receptors (B1R and B2R) in a closed tibial fracture pain model by using knockout mice for B1R (B1KO) or B2R (B2KO) and wild-type (WT) mice treated with antagonists for B1R (SSR 240612 and R954) and B2R (HOE140) or vehicle. A cyclooxygenase (COX) inhibitor (ketoprofen) and an antagonist (SB366791) of Transient Receptor Potential Vaniloid1 (TRPV1) were also investigated since these pathways are associated with BK-induced pain in other models. The impact on mechanical and thermal hyperalgesia and locomotion was assessed by behavior tests. Gene expression of B1R and B2R and spinal cord expression of c-Fos were measured by RT-PCR and immunohistochemistry, respectively.

Results: B1KO and B2KO mice demonstrated a reduction in post-fracture pain sensitivity compared to WT mice that was associated with decreased c-Fos expression in the ipsilateral spinal dorsal horn in B2KO. B1R and B2R mRNA and protein levels were markedly enhanced at the fracture site. B1R and B2R antagonists and inhibition of COX and TRPV1 pathways reduced pain in WT. However, the analgesic effect of the COX-1/COX-2 inhibitor disappeared in B1KO and B2KO. In contrast, the analgesic effect of the TRPV1 antagonist persisted after gene deletion of either receptor.

Conclusions: It is suggested that B1R and B2R activation contributes significantly to tibial fracture pain through COX. Hence, B1R and B2R antagonists appear potential therapeutic agents to manage post fracture pain.

Keywords: Analgesia; B1 receptor; B2 receptor; Bradykinin; Fracture; Orthopedic; Pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bradykinin B1 Receptor Antagonists / pharmacology
  • Bradykinin B2 Receptor Antagonists / pharmacology
  • Cyclooxygenase Inhibitors / pharmacology
  • Disease Models, Animal
  • Inflammation / etiology
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pain / drug therapy
  • Pain / physiopathology*
  • Pain / prevention & control
  • Pain Measurement
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • RNA, Messenger
  • Receptor, Bradykinin B1 / deficiency
  • Receptor, Bradykinin B1 / genetics
  • Receptor, Bradykinin B1 / physiology*
  • Receptor, Bradykinin B2 / deficiency
  • Receptor, Bradykinin B2 / genetics
  • Receptor, Bradykinin B2 / physiology*
  • TRPV Cation Channels / antagonists & inhibitors
  • Tibial Fractures / complications
  • Tibial Fractures / pathology
  • Tibial Fractures / physiopathology*
  • Translational Research, Biomedical


  • Bradykinin B1 Receptor Antagonists
  • Bradykinin B2 Receptor Antagonists
  • Cyclooxygenase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • TRPV Cation Channels
  • TRPV1 protein, mouse