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Updated: Jun 25, 2025
Determining heat and mechanical pain threshold in inflamed skin of human subjects
Published on: January 14, 2009
Methylene blue dose-dependently induces cutaneous inflammation and heat hyperalgesia in a novel rat model
Ratan K Banik1, Twan Sia1,2, Malcolm E Johns1
1Department of Anesthesiology, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
Abstract:
Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1β and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1β, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.
Insights
Methylene blue (MB) can cause skin toxicity. High MB concentrations (1%) induce inflammation and pain in rats, suggesting careful IV administration is needed to prevent adverse cutaneous reactions.
Area of Science:
- Pharmacology
- Toxicology
- Dermatology
Background:
- Methylene blue (MB) is used to treat vasoplegic patients post-cardiac surgery.
- While generally safe, MB extravasation can cause cutaneous toxicity.
- Understanding MB's skin toxicity mechanisms is crucial for safe administration.
Purpose of the Study:
- To characterize Methylene blue-induced cutaneous toxicity in a rat model.
- To investigate the underlying molecular mechanisms of MB skin toxicity.
- To provide guidance on safe Methylene blue administration routes and concentrations.
Main Methods:
- Induction of cutaneous toxicity via plantar paw injection of varying Methylene blue concentrations (1%, 0.1%, 0.01%) in Sprague-Dawley rats.
- Assessment of paw swelling, histological skin changes, and thermal/mechanical hyperalgesia.
- Global transcriptomic analysis (RNAseq) and quantitative PCR (qPCR) to identify molecular pathways involved.
Main Results:
- 1% Methylene blue caused significant paw swelling and heat hyperalgesia, unlike lower concentrations.
- RNAseq revealed differential gene expression related to leukocyte infiltration, lipids, and myeloid cell apoptosis.
- Key regulatory hubs identified include IL-1β and Fos, with a significant increase in IL-6 mRNA.
Conclusions:
- Methylene blue infiltration into cutaneous tissue induces a dose-dependent pro-inflammatory response.
- Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Fos signaling pathways are implicated in MB-induced skin toxicity.
- Dilute MB should be administered intravenously via peripheral lines; concentrated MB (1%) requires central venous catheterization to mitigate cutaneous risks.
