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Cited by 18Pain Mechanisms and TreatmentsPain Management and TreatmentNF-κB Signaling Pathways

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Lidocaine attenuates CFA‑induced inflammatory pain in rats by regulating the MAPK/ERK/NF‑κB signaling pathway

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Zhang, Shuli, Li, Yan, Tu, Yingjun·2021·Experimental and Therapeutic Medicine
DOI 10.3892/etm.2021.9643PMC PMC7818540
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Abstract

Lidocaine is a commonly used local anesthetic that also confers analgesic effects, resistance to hyperalgesia and anti-inflammatory properties. The present study aimed to explore the effects of lidocaine on complete Freund's adjuvant (CFA)-induced inflammatory pain. In the present study, rats were subcutaneously injected with CFA to investigate the molecular mechanisms associated with lidocaine in an inflammation-induced pain model. Firstly, CFA was subcutaneously injected into the paws of Sprague-Dawley rats, following which lidocaine or saline and the ERK agonist recombinant human epidermal growth factor (rh-EGF) were injected via the tail vein. Rat behavior was then assessed at 0 and 4 h, 1, 4, 7 and 14 days after CFA treatment. Proinflammatory cytokine levels in the serum were measured using ELISA. Western blotting was performed to detect the protein levels of phosphorylated (p)-ERK1/2, ERK1/2 and NF-κB subunits p-p65 and p65. Reverse transcription-quantitative PCR was used to measure the mRNA expression of ERK1/2 and p65 in rat spinal cord tissues. The results showed that injection of CFA significantly reduced the mechanical withdrawal threshold, thermal withdrawal latency and the frequency of responses to cold stimulation in rats, whilst promoting tumor necrosis factor-α, interleukin (IL)-1β, IL-6 levels in addition to ERK1/2, p65 protein phosphorylation. These effects were alleviated by lidocaine treatment. Furthermore, treatment with rh-EGF reversed the protective effects of lidocaine on inflammatory pain caused by CFA. In conclusion, lidocaine inhibits the inflammatory response and pain through the MAPK/ERK/NF-κB pathway in a rat model of pain induced by CFA.

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Figure 1 Effects of lidocaine on the behavior of CFA-treated rats. Rats were treated with lidocaine and CFA or CFA alone before rat behavior was assessed. (A) The effects of lidocaine on the MWT of CFA-treated rats. (B) The effects of lidocaine on the TWL of CFA-treated rats. (C) The effects of lidocaine on frequency responses to cold stimulation by CFA-treated rats. Data are presented as the mean ± standard deviation. **P<0.01 vs. Control; #P<0.05 and ##P<0.01 vs. CFA. CFA, complete Freund's adjuvant; MWT, mechanical withdrawal threshold; TWL, thermal withdrawal latency.
Figure 1 Effects of lidocaine on the behavior of CFA-treated rats. Rats were treated with lidocaine and CFA or CFA alone before rat behavior was assessed. (A) The effects of lidocaine on the MWT of CFA-treated rats. (B) The effects of lidocaine on the TWL of CFA-treated rats. (C) The effects of lidocaine on frequency responses to cold stimulation by CFA-treated rats. Data are presented as the mean ± standard deviation. **P<0.01 vs. Control; #P<0.05 and ##P<0.01 vs. CFA. CFA, complete Freund's adjuvant; MWT, mechanical withdrawal threshold; TWL, thermal withdrawal latency.CC BY-NC-ND · PubMed Central
Figure 2 Effects of lidocaine on the levels of pro-inflammatory factors in the serum of CFA-treated rats. After 4 days of CFA treatment, the effects of lidocaine on the levels pro-inflammatory mediators were evaluated using ELISA. The effect of lidocaine on (A) TNF-α, (B) IL-1β and (C) IL-6 levels in CFA-treated rats. Data are presented as the mean ± standard deviation. **P<0.01 vs. Control; #P<0.05 and ##P<0.01 vs. CFA. CFA, complete Freund's adjuvant; TNF, tumor necrosis factor; IL, interleukin.
Figure 2 Effects of lidocaine on the levels of pro-inflammatory factors in the serum of CFA-treated rats. After 4 days of CFA treatment, the effects of lidocaine on the levels pro-inflammatory mediators were evaluated using ELISA. The effect of lidocaine on (A) TNF-α, (B) IL-1β and (C) IL-6 levels in CFA-treated rats. Data are presented as the mean ± standard deviation. **P<0.01 vs. Control; #P<0.05 and ##P<0.01 vs. CFA. CFA, complete Freund's adjuvant; TNF, tumor necrosis factor; IL, interleukin.CC BY-NC-ND · PubMed Central
Figure 3 Effects of lidocaine on the MAPK/ERK/NF-κB signaling pathway in CFA-treated rats. To investigate the pathways in this rat model, after 4 days of CFA treatment, western blotting was used to measure ERK1/2 and p65 phosphorylation in rat spinal cord tissues. Reverse transcription-quantitative PCR was also used to detect the mRNA expression of ERK1/2 and p65. (A) The effect of lidocaine on p-ERK1/2 levels and the p-ERK1/2/ERK ratio in CFA-induced rats, (B) which was quantified. (C) The effect of lidocaine on ERK1/2 mRNA expression in CFA-treated rats. (D) The effect of lidocaine on p-p65 levels and the p-p65/p65 ratio in CFA-induced rats, (E) which was quantified. (F) The effect of lidocaine on p65 mRNA expression in CFA-treated rats. **P<0.01 vs. Control; #P<0.05 and ##P<0.01 vs. CFA. CFA, complete Freund's adjuvant; p, phosphorylated.
Figure 3 Effects of lidocaine on the MAPK/ERK/NF-κB signaling pathway in CFA-treated rats. To investigate the pathways in this rat model, after 4 days of CFA treatment, western blotting was used to measure ERK1/2 and p65 phosphorylation in rat spinal cord tissues. Reverse transcription-quantitative PCR was also used to detect the mRNA expression of ERK1/2 and p65. (A) The effect of lidocaine on p-ERK1/2 levels and the p-ERK1/2/ERK ratio in CFA-induced rats, (B) which was quantified. (C) The effect of lidocaine on ERK1/2 mRNA expression in CFA-treated rats. (D) The effect of lidocaine on p-p65 levels and the p-p65/p65 ratio in CFA-induced rats, (E) which was quantified. (F) The effect of lidocaine on p65 mRNA expression in CFA-treated rats. **P<0.01 vs. Control; #P<0.05 and ##P<0.01 vs. CFA. CFA, complete Freund's adjuvant; p, phosphorylated.CC BY-NC-ND · PubMed Central
Figure 4 Protective effects of lidocaine on the behavior CFA-treated rats is reversed by rh-EGF. CFA treated rats were treated with the ERK agonist rh-EGF based on aforementioned studies. The effect of lidocaine and rh-EGF on the (A) mechanical withdrawal threshold, (B) thermal withdrawal latency and (C) frequency responses to cold stimulation by CFA-induced rats were analyzed at 0 and 4 h, 1, 4, 7 or 14 days after CFA treatment. The effect of lidocaine and rh-EGF on the serum levels of (D) TNF-α, (E) IL-1β and (F) IL-6 in CFA-treated rats were determined at 4 days after CFA treatment. **P<0.01 vs. CFA + lidocaine. CFA, complete Freund's adjuvant; rh-EGF, recombinant human epidermal growth factor; TNF, tumor necrosis factor; IL, interleukin.
Figure 4 Protective effects of lidocaine on the behavior CFA-treated rats is reversed by rh-EGF. CFA treated rats were treated with the ERK agonist rh-EGF based on aforementioned studies. The effect of lidocaine and rh-EGF on the (A) mechanical withdrawal threshold, (B) thermal withdrawal latency and (C) frequency responses to cold stimulation by CFA-induced rats were analyzed at 0 and 4 h, 1, 4, 7 or 14 days after CFA treatment. The effect of lidocaine and rh-EGF on the serum levels of (D) TNF-α, (E) IL-1β and (F) IL-6 in CFA-treated rats were determined at 4 days after CFA treatment. **P<0.01 vs. CFA + lidocaine. CFA, complete Freund's adjuvant; rh-EGF, recombinant human epidermal growth factor; TNF, tumor necrosis factor; IL, interleukin.CC BY-NC-ND · PubMed Central
Figure 5 Effects of lidocaine on the MAPK/ERK/NF-κB pathway in CFA-induced rats is reversed by rh-EGF. Effects of lidocaine on the MAPK/ERK/NF-κB pathway in CFA-induced rats were studied at 4 days after CFA treatment. (A) The effect of lidocaine and rh-EGF on p-ERK1/2 levels and the p-ERK1/2/ERK ratio of CFA-induced rats, (B) which was quantified. (C) The effect of lidocaine and rh-EGF on ERK1/2 mRNA expression in CFA-treated rats. (D) The effect of lidocaine and rh-EGF on p-p65 levels and the p-p65/p65 ratio in CFA-treated rats, (E) which was quantified. (F) The effect of lidocaine and rh-EGF on p65 mRNA expression in CFA-treated rats. Data are presented as the mean ± standard deviation. **P<0.01 vs. CFA + lidocaine. CFA, complete Freund's adjuvant; p-, phosphorylated; rh-EGF, recombinant human epidermal growth factor.
Figure 5 Effects of lidocaine on the MAPK/ERK/NF-κB pathway in CFA-induced rats is reversed by rh-EGF. Effects of lidocaine on the MAPK/ERK/NF-κB pathway in CFA-induced rats were studied at 4 days after CFA treatment. (A) The effect of lidocaine and rh-EGF on p-ERK1/2 levels and the p-ERK1/2/ERK ratio of CFA-induced rats, (B) which was quantified. (C) The effect of lidocaine and rh-EGF on ERK1/2 mRNA expression in CFA-treated rats. (D) The effect of lidocaine and rh-EGF on p-p65 levels and the p-p65/p65 ratio in CFA-treated rats, (E) which was quantified. (F) The effect of lidocaine and rh-EGF on p65 mRNA expression in CFA-treated rats. Data are presented as the mean ± standard deviation. **P<0.01 vs. CFA + lidocaine. CFA, complete Freund's adjuvant; p-, phosphorylated; rh-EGF, recombinant human epidermal growth factor.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Zhang, S., Li, Y., & Tu, Y.
Affiliations
  • First Affiliated Hospital of Xinjiang Medical University (CN)
  • Yili Friendship Hospital (CN)
Corresponding author
Tu, Yingjun
ORCID
Li, Yan
Venue
Experimental and Therapeutic Medicine
Publisher
Spandidos Publications
Published
2021-01-14
Volume
21
Issue
3
Pages
211-211
ISSN
  • 1792-0981 (ISSN-L)
  • 1792-1015
DOI
10.3892/etm.2021.9643
PMC
PMC7818540
OpenAlex
W3118616807
Cited by
18
References
44
Citations by year
2026: 2 · 2025: 2 · 2024: 7 · 2023: 4 · 2022: 1 · 2021: 2
FWCI
2.20
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Experimental and Therapeutic Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
lidocaine, inflammatory pain, complete Freund's adjuvant, ERK signaling, NF-κB signaling, ERK1/2 phosphorylation, recombinant human epidermal growth factor, inflammatory cytokines, TNF-α, IL-1β, interleukin-6, spinal cord, local anesthetic analgesia, mechanical withdrawal threshold

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Zhang, S., Li, Y., & Tu, Y. (2021). Lidocaine attenuates CFA‑induced inflammatory pain in rats by regulating the MAPK/ERK/NF‑κB signaling pathway. Experimental and Therapeutic Medicine. https://doi.org/10.3892/etm.2021.9643