Abstract
BackgroundTibial 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.MethodsThis 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.ResultsB1KO 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.ConclusionsIt 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.
Highlights
Tibial fracture is associated with inflammatory reaction leading to severe pain syndrome
Tibial fracture models were first developed in rats [11] and have been used to investigate several systems involved in the so-called Complex Regional Pain Syndrome (CRPS) [12]
Behavioral pain measurements were significantly but differently reduced both in knockout mice for B1R (B1KO) and knockout mice for B2R (B2KO) mice when compared to WT mice (Fig. 1)
Summary
Tibial fracture is associated with inflammatory reaction leading to severe pain syndrome. The same authors reported that IL-1beta contributes to chronic regional nociceptive sensitization after fracture, possibly by stimulating NGF overexpression in keratinocytes [16,17,18,19,20] These studies support the involvement of inflammatory cytokines, including TNF-alpha [14, 15] in the nociceptive sensitization after fracture. It has been proposed that the upregulation of cytokine production depends on the activation of multi-protein complexes termed inflammasomes, which could be involved in the processing and activation of pro-inflammatory cytokines [16,17,18,19,20] Most of these investigations have focused on the chronic signaling pathways leading to post-traumatic chronic inflammation and pain mechanisms rather than on the potential upstream targets. Pro-inflammatory cytokines are known to induce and upregulate B1R through the activation of the transcriptional nuclear factor NF-kappaB in several experimental models [21,22,23,24]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
