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

Abstract

1 The cleavage of haeme by haeme oxygenase (HO) yields carbon monoxide (CO), a biologically active molecule which exerts most of its eects via activation of soluble guanylate cyclase (sGC). In the present study, we tested the hypothesis that endogenous CO could modulate in¯ammatory hyperalgesia. The intensity of hyperalgesia was investigated in a model of mechanical nociceptor hypersensitivity in rats. 2 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. 3 The mechanical hypersensitivity evoked by i.pl. injection of interleukin-1b (IL-1b), tumour necrosis factor-a (TNF-a), but not interleukin-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 hypersensitivity evoked by IL-1b, but not PGE 2 . Furthermore, i.pl. administration of the gas CO reduced the hypersensitivity elicited by PGE 2 . 5 The inhibitory eect 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 eect of CO is mediated via cyclic GMP. 6 Finally, the inhibitory eect 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. 7 In conclusion, the results presented in this paper imply that endogenously CO produced by HO plays an anti-hyperalgesic role in in¯amed paws, probably by increasing the intracellular levels of cyclic GMP in the primary aerent neurone.

Antinociception synergy between the peripheral and spinal sites of the heme oxygenase-carbon monoxide pathway

“…In agreement, evidence has been accumulated demonstrating that the HO-CO-cGMP pathway plays a role in mechanical hypernociception (10) and in the formalin test (11). Now the knowledge has been extended to the possible functional synergy between the spinal and peripheral HO-CO pathway in the nociceptive response.…”

“…CO has also been reported to participate in both stress-and endotoxin-induced fever (7,8), in hypoxia-induced hypothermia (9) and to have an anti-hyperalgesic effect in inflamed paws, probably by increasing intracellular levels of cGMP in primary afferent neurons. These data have been obtained using both the hypernociception induced by carrageenan (10), and the inflammatory formalin model (11). Moreover, the spinal HO-CO pathway may also have an anti-hyperalgesic effect (12).…”

H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

“…HO-1 upregulation has been associated with an anti-inflammatory and antinociceptive effect in the formalin test [10]. CO, which is produced by HO, has also been found to inhibit inflammatory hyperalgesia in the paw [47]. CORM-2 may be selected to release carbon monoxide [48].…”

Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF-κB activation

“…Co-treatment with an HO-1 inducer increased the antinociceptive effects of opioids and cannabinoids through activation of cGMP/PKG/ATP-sensitive potassium channel pathway in a model of CFAinduced pain [66]. On the other hand, the administration of HO-1 inhibitor increases mechanical hyperalgesia [67]. Several antioxidant molecules can increase HO-1 expression, and curcumin is one of them [27,28,68], a feature that we verified in our model with a 9.5-fold increase of expression.…”