Nicotinamide adenine dinucleotide phosphate/neuronal nitric oxide synthase-positive neurons in the trigeminal subnucleus caudalis involved in tooth pulp nociception.

Sensory information on facial structures, including teeth pulp, periodontium, and gingiva, is relayed in the trigeminal complex. Tooth pulp inflammation constitutes a common clinical problem, and this peripheral injury can induce neuroplastic changes in trigeminal nociceptive neurons. There is considerable evidence that the trigeminal subnucleus caudalis (Vc) is the principal relay for trigeminal nociceptive information as well as modulation of the painful stimuli. Glutamatergic primary afferents innervating the tooth pulp project to the most superficial laminae of the Vc. N-methyl-D-aspartate receptor stimulation leads to the activation of the enzyme nitric oxide synthase (NOS), which synthesizes the free radical nitric oxide (NO). This enzyme is expressed mainly in lamina II interneurons, and in a small number of cells in lamina I as well as in deep laminae projection neurons of Vc. In the present study, we analyzed the temporal changes in neuronal NOS (nNOS) in Vc local circuitries after unilateral intermediate molar pulp injury. Our results demonstrate that a peripheral dental pulp injury leads to neuroplastic changes in the relative amount and activity of nNOS enzyme. Moreover, after a period of time, the nitrergic system shifts to the initial values, independently of the persistence of inflammation in the pulp tissues.

Caspase-1 is involved in the genesis of inflammatory hypernociception by contributing to peripheral IL-1ß maturation.

BACKGROUND: Caspase-1 is a cysteine protease responsible for the processing and secretion of IL-1ß and IL-18, which are closely related to the induction of inflammation. However, limited evidence addresses the participation of caspase-1 in inflammatory pain. Here, we investigated the role of caspase-1 in inflammatory hypernociception (a decrease in the nociceptive threshold) using caspase-1 deficient mice (casp1-/-). RESULTS: Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. The production of cytokines, PGE2 and neutrophil migration were evaluated by ELISA, radioimmunoassay and myeloperoxidase activity, respectively. The interleukin (IL)-1ß and cyclooxygenase (COX)-2 protein expression were evaluated by western blotting. The mechanical hypernociception induced by intraplantar injection of carrageenin, tumour necrosis factor (TNF)α and CXCL1/KC was reduced in casp1-/- mice compared with WT mice. However, the hypernociception induced by IL-1ß and PGE2 did not differ in WT and casp1-/- mice. Carrageenin-induced TNF-α and CXCL1/KC production and neutrophil recruitment in the paws of WT mice were not different from casp1-/- mice, while the maturation of IL-1ß was reduced in casp1-/- mice. Furthermore, carrageenin induced an increase in the expression of COX-2 and PGE2 production in the paw of WT mice, but was reduced in casp1-/- mice. CONCLUSION: These results suggest that caspase-1 plays a critical role in the cascade of events involved in the genesis of inflammatory hypernociception by promoting IL-1ß maturation. Because caspase-1 is involved in the induction of COX-2 expression and PGE2 production, our data support the assertion that caspase-1 is a key target to control inflammatory pain.

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.

Oxido nítrico en la nocicepción / Nitric oxide and nociception

Las investigaciones en el campo del dolor y de la analgesia se están enfocando hacia los eventos celulares y moleculares subyacentes a los mecanismos de dolor crónico. En particular, mucha atención está recibiendo el óxido nítrico (ON), un nuevo tipo de neurotransmisor. El ON es un radical libre gaseoso e inestable que resulta de la oxidación de la L-arginina a L-citrulina en una reacción catalizada por la sintasa del óxido nítrico. El ON cumple un papel de molécula citotóxica de macrófagos activados y de relajante de músculo liso. Además de estas funciones, el ON actúa como neuromodulador y/o neurotransmisor en el sistema nervioso. Reportes recientes han comenzado a definir el papel del ON en los procesos nociceptivos a nivel de la médula espinal. Asociado a receptores sensibles al N-metil-D-aspartato (NMDA), parece estar involucrado en los mecanismos suyacentes de la hiperalgesia térmica, involucrado en la facilitación de reflejos térmicos. Es más, parece que la producción sostenida del On y la subsecuente activación de la guanilato ciclasa soluble en la médula espinal lumbar, son condiciones requeridas para el mantenimiento de la hiperalgesia térmica producida en modelos del dolor persistente. La inhibición de la sintasa del ON con nitro-L-arginina bloquea la tolerancia a la morfina en ratones. La nitro-L-arginina también es capaz de revertir lentamente tolerancia preexistente, además de reducir la dependencia y de revertir la dependencia a la droga previemente establecida. La acción del ON es selectivo para la tolerancia y dependencia a receptores del subtipo µ