title: Low-dose endotoxin potentiates capsaicin-induced pain in man: evidence for a pain neuroimmune connection.
abstract: Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50μg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Mara
authors.initials: M
authors.lastname: Buijs
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tuke
authors.forename: Yuen Hei
authors.initials: YH
authors.lastname: Kwok
authors.forename: Melanie
authors.initials: M
authors.lastname: Gentgall
authors.forename: Desmond
authors.initials: D
authors.lastname: Williams
authors.forename: Paul
authors.initials: P
authors.lastname: Rolan
mesh_terms: D000328:Adult; D002211:Capsaicin; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D051197:Toll-Like Receptor 4; C044101:endotoxin, Escherichia coli; D002211:Capsaicin