Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Apr;34(2):321-329.
doi: 10.1007/s12264-017-0194-2. Epub 2017 Dec 5.

Peripheral Leptin Signaling Mediates Formalin-Induced Nociception

Affiliations

Peripheral Leptin Signaling Mediates Formalin-Induced Nociception

Zhi-Jing Hu et al. Neurosci Bull. 2018 Apr.

Abstract

Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high-fat diet, we found that: (1) the acute thermal pain sensory threshold did not change in obese mice; (2) the model obese mice had fewer nociceptive responses in formalin-induced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation; (3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice, indicating the dysmodulation of topical leptin-leptin receptor signaling in these mice; and (4) leptin-leptin receptor signaling-deficient mice (ob/ob and db/db) or leptin-leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wild-type mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin-leptin receptor pathway could be a peripheral target against acute inflammatory pain.

Keywords: Formalin test; Leptin; Nociception; Obesity.

PubMed Disclaimer

Conflict of interest statement

The authors declared no conflict of interests regarding the publication of this article.

Figures

Fig. 1
Fig. 1
Body weight, body composition, and plasma leptin levels of obese mice and chow diet mice. The high-fat diet caused increased weight gain (A) and fat gain (B) compared with chow diet controls; plasma leptin levels were increased significantly after 12 weeks on the high-fat diet administration (C); n = 4–8/group, mean ± SEM, high-fat diet vs chow diet, ***P < 0.001.
Fig. 2
Fig. 2
Acute thermal nociceptive responses and spontaneous locomotor activity of obese mice and chow diet mice. The high-fat diet group’s responses to acute noxious heat (A Paw withdrawal latency; B Tail-flick latency) were the same as the chow diet controls; the spontaneous locomotor activity of both groups were not statistically different (C Time course; D Total distance traveled); n = 8/group, mean ± SEM.
Fig. 3
Fig. 3
Formalin-induced nociceptive responses of obese mice and chow diet mice. The nociceptive behavior during the A first (0–9 min) and B second (10–45 min) phases after 0.25%, 0.5%, and 1% formalin injection was measured as the number of flinching motions made by the injected paw; n = 8/group, mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001, high-fat diet vs chow diet.
Fig. 4
Fig. 4
Formalin-induced nociceptive responses of mice 3 weeks after switching to a chow diet. A Flowchart of this study; the decreased nociceptive behavior of obese mice during the (B) first (0–9 min) and (C) second (10–45 min) phases after 1% formalin injection significantly recovered and was associated with decreased body weight (D), fat content (E), and leptin levels in plasma (F); n = 8/group, mean ± SEM, *P < 0.05, ** P < 0.01, ***P < 0.001, obese chow diet vs obese high fat diet.
Fig. 5
Fig. 5
Formalin-induced inflammatory nociceptive responses of wild-type mice and leptin–leptin receptor signaling-deficient mice. The formalin-induced nociceptive behavior was decreased in ob/ob (A, B, and C) and db/db mice (D, E and F) during the first (0–9 min) and second (10–45 min) phases; n = 8/group, mean ± SEM; *P < 0.05, **P < 0.01, ob/ob or db/db mice vs wild-type mice.
Fig. 6
Fig. 6
STAT activation in topical paw skin 2 h after leptin injection (0.1 µg/paw); p-STAT3/STAT3 expression in chow diet (A) and high-fat diet mice (B); n = 4/group, mean ± SEM, *P < 0.05 (student t test); NS, not significant; leptin vs saline group.
Fig. 7
Fig. 7
Effects of leptin antagonist and AG 490 on formalin-induced nociceptive responses in normal mice; pretreatment with the leptin antagonist at 0.3 to 3 µg inhibited formalin-induced nociceptive behavior during the first (A 0–9 min) and second (B 10–45 min) phases in a dose-dependent manner; pretreatment with the leptin signaling pathway inhibitor AG 490 (JAK2 inhibitor) at 1 to 10 µg inhibited formalin-induced nociceptive behavior during the first (C 0–9 min) and second (D 10–45 min) phases in a dose-dependent manner; n = 7–8/group, mean ± SEM; *P < 0.05, **P < 0.01, leptin antagonist or AG 490 vs vehicle group.

References

    1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311:806–814. doi: 10.1001/jama.2014.732. - DOI - PMC - PubMed
    1. Rossi HL, Broadhurst KA, Luu ASK, Lara O, Kothari SD, Mohapatra DP, et al. Abnormal trigeminal sensory processing in obese mice. Pain. 2016;157:235–246. doi: 10.1097/j.pain.0000000000000355. - DOI - PMC - PubMed
    1. Younger J, Kapphahn K, Brennan K, Sullivan SD, Stefanick ML. Association of leptin with body pain in women. J Women Health. 2016;25:752–760. doi: 10.1089/jwh.2015.5509. - DOI - PMC - PubMed
    1. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995;1:1311–1314. doi: 10.1038/nm1295-1311. - DOI - PubMed
    1. Totsch SK, Waite ME, Tomkovich A, Quinn TL, Gower BA, Sorge RE. Total western diet alters mechanical and thermal sensitivity and prolongs hypersensitivity following complete Freund’s adjuvant in mice. J Pain. 2016;17:119–125. doi: 10.1016/j.jpain.2015.10.006. - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources