TNF-alpha neutralizing antibody blocks thermal sensitivity induced by compound 48/80-provoked mast cell degranulation [v1; ref status: indexed, http://f1000r.es/1mq]

• Main Authors: Devavani Chatterjea, Luisa Paredes, Tijana Martinov, Evelyn Balsells, Juliann Allen, Akilah Sykes, Alyssa Ashbaugh
• Format: Article
• Language: English
• Published: F1000 Research Ltd 2013-08-01
• Series: F1000Research
• Subjects: Allergy & Hypersensitivity; Leukocyte Signaling & Gene Expression
• Online Access: http://f1000research.com/articles/2-178/v1

Background:  Neuro-inflammatory circuits in the tissue regulate the complex pathophysiology of pain.  Protective nociceptive pain serves as an early warning system against noxious environmental stimuli.  Tissue-resident mast cells orchestrate the increased thermal sensitivity following injection of basic secretagogue compound 48/80 in the hind paw tissues of ND4 mice.  Here we investigated the effects of pre-treatment with TNF-α neutralizing antibody on compound 48/80-provoked thermal hyperalgesia.  Methods:  We treated ND4 Swiss male mice with intravenous anti-TNF-α antibody or vehicle 30 minutes prior to bilateral, intra-plantar compound 48/80 administration and measured changes in the timing of hind paw withdrawal observed subsequent to mice being placed on a 51oC hotplate.  We also assessed changes in tissue swelling, TNF-α gene expression and protein abundance, mast cell degranulation, and neutrophil influx in the hind paw tissue.  Findings:  We found that TNF-α neutralization significantly blocked thermal hyperalgesia, and reduced early tissue swelling. TNF-α neutralization had no significant effect on mast cell degranulation or neutrophil influx into the tissue, however.  Moreover, no changes in TNF-α protein or mRNA levels were detected within 3 hours of administration of compound 48/80.  Interpretation:  The neutralizing antibodies likely target pre-formed TNF-α including that stored in the granules of tissue-resident mast cells. Pre-formed TNF-α, released upon degranulation, has immediate effects on nociceptive signaling prior to the induction of neutrophil influx.  These direct effects on nociceptors are abrogated by TNF-α blockade resulting in compromised nociceptive withdrawal responses to acute, harmful environmental stimuli.