Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity

1 The cleavage of haeme by haeme oxygenase (HO) yields carbon monoxide (CO) , a biologically active molecule which exerts most of its effects via activ ation of soluble guanylate cyclase (sGC). In the present study, we tested t he hypothesis that endogenous CO could modulate inflammatory hyperalgesia. The intensity of hyperalgesia was investigated in a model of mechanical noc iceptor hypersensitivity in rats. 2 The intra-plantar (i.pl.) administration of the HO inhibitor, ZnDPBG (Zin c deuteroporphyrin 2,4-bis glycol), potentiated in a dose-dependent manner the mechanical nociceptor hypersensitivity evoked by i.pl. administration o f carrageenan. 3 The mechanical hypersensitivity evoked by i.pl. injection of interleukin- 1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), but not inter leukin-8 (IL-8), prostaglandin E-2 (PGE(2)) or dopamine, was also enhanced by ZnDPBG. 4 Moreover, the haeme (HO substrate) injection in the paws reduced the hype rsensitivity evoked by IL-I beta, but not PGE(2). Furthermore, i.pl. admini stration of the gas CO reduced the hypersensitivity elicited by PGE(2). 5 The inhibitory effect of haeme and CO upon mechanical nociceptor hypersen sitivity were counteracted by a soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one), suggesting that this ef fect of CO is mediated via cyclic GMP. 6 Finally, the inhibitory effect of CO upon mechanical nociceptor hypersens itivity was prevented by the NO synthase blocker, L-NMMA (N-G-monomethyl L- arginine), suggesting that the impairment of mechanical hypersensitivity el icited by CO depends on the integrity of the NO pathway. 7 In conclusion, the results presented in this paper imply that endogenousl y CO produced by HO plays an anti-hyperalgesic role in inflamed paws, proba bly by increasing the intracellular levels of cyclic GMP in the primary aff erent neurone.