title: Intravenous adenosine activates diffuse nociceptive inhibitory controls in humans.
abstract: Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and Aδ fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 μg·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved.
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Groupe Hospitalier Pitié Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale, Paris, France;
authors.forename: Capucine
authors.initials: C
authors.lastname: Morélot-Panzini
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Alexandre
authors.initials: A
authors.lastname: Demoule
authors.forename: Mathieu
authors.initials: M
authors.lastname: Raux
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Fiamma
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Willer
authors.forename: Thomas
authors.initials: T
authors.lastname: Similowski
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000328:Adult; D002245:Carbon Dioxide / Q000378:metabolism; D002637:Chest Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004417:Dyspnea / Q000378:metabolism / Q000503:physiopathology; D004558:Electric Stimulation / Q000379:methods; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D002245:Carbon Dioxide; D000241:Adenosine
keywords: C fibers; adenosine; counterirritation; dyspnea; pain