Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity.
The cleavage of haeme by haeme oxygenase (HO) yields carbon monoxide (CO), a biologically active molecule which exerts most of its effects via activation of soluble guanylate cyclase (sGC). In the present study, we tested the hypothesis that endogenous CO could modulate inflammatory hyperalgesia. The intensity of hyperalgesia was investigated in a model of mechanical nociceptor hypersensitivity in rats. The intra-plantar (i.pl.) administration of the HO inhibitor, ZnDPBG (Zinc deuteroporphyrin 2,4-bis glycol), potentiated in a dose-dependent manner the mechanical nociceptor hypersensitivity evoked by i.pl. administration of carrageenan. The mechanical hypersensitivity evoked by i.pl. injection of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), but not interleukin-8 (IL-8), prostaglandin E(2) (PGE(2)) or dopamine, was also enhanced by ZNDPBG: Moreover, the haeme (HO substrate) injection in the paws reduced the hypersensitivity evoked by IL-1beta, but not PGE(2). Furthermore, i.pl. administration of the gas CO reduced the hypersensitivity elicited by PGE(2). The inhibitory effect of haeme and CO upon mechanical nociceptor hypersensitivity were counteracted by a soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one), suggesting that this effect of CO is mediated via cyclic GMP. Finally, the inhibitory effect of CO upon mechanical nociceptor hypersensitivity was prevented by the NO synthase blocker, L-NMMA (N(G)-monomethyl L-arginine), suggesting that the impairment of mechanical hypersensitivity elicited by CO depends on the integrity of the NO pathway. In conclusion, the results presented in this paper imply that endogenously CO produced by HO plays an anti-hyperalgesic role in inflamed paws, probably by increasing the intracellular levels of cyclic GMP in the primary afferent neurone.
Steiner
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Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, USP, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, Brazil.
Branco
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Cunha
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D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology; D002351:Carrageenan; D016207:Cytokines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008465:Mechanoreceptors / Q000201:enzymology* / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D009619:Nociceptors / Q000201:enzymology* / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D002248:Carbon Monoxide; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006419:Heme Oxygenase (Decyclizing); D006162:Guanylate Cyclase