Peripheral involvement of the nitric oxide–cGMP pathway in the indomethacin-induced antinociception in rat

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Abstract

The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0±3.0 and 149.7±18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, NG-l-nitro-arginine methyl ester (l-NAME) (72.9±10.7 vs. 149.7±18.0 au, P<0.05). On the other hand, local administration of l-arginine (a NO synthase substrate) or sodium nitroprusside (a non-enzymatic NO donor) each increased in almost 40% the antinociceptive effect of indomethacin (230.9±12.6 and 226.6±9.7 vs. 149.7±18.0 au, P<0.05), whereas d-arginine (the inactive isomer of arginine) had no effect on the indomethacin antinociceptive response (208.0±34.9 vs. 149.7±18.0 au). These results suggest that, the antinociceptive effect of indomethacin involves, at least in part, the NO–cyclic GMP pathway at peripheral level.

Introduction

Nitric oxide (NO) is involved in a variety of physiological functions such as vasodilatation, macrophage cytotoxicity, central nervous system plasticity and nociceptive processing (Schuman and Madison, 1994, Moncada, 1997). NO is synthesized from l-arginine through the action of several NO synthase subtypes, and it activates soluble guanylate cyclase, which in turn gives rise to increased levels of cyclic GMP (cGMP) (Meller and Gebhart, 1993). Evidence has been provided to suggest that NO and cGMP play a role in antinociception since local administration of l-arginine was reported to produce antinociception in rats with carragenin-induced hyperalgesia, and this effect was blocked by NO synthesis inhibitors and soluble guanylate cyclase inhibitors (Duarte et al., 1990). In accordance with these findings, local administration of non-enzymatic NO donors was found to inhibit prostaglandin- and carragenin-induced hyperalgesia; this effect was prevented by guanylyl cyclase inhibitors but not by NO synthase inhibitors (Ferreira et al., 1991).

It has been suggested, on the other hand, that inflammatory pain involves nociceptor sensitisation and that cyclic adenosine monophosphate (cAMP) may play an important role in this process (Ferreira and Nakamura, 1979). These observations support the hypothesis that a neuronal balance between cAMP and cGMP concentrations may be critical for the upward or downward functional regulation of nociceptors (Ferreira and Nakamura, 1979, Duarte et al., 1990). More recently, the antinociceptive effects of certain non-steroidal anti-inflammatory drugs (NSAIDs), such as dipyrone, diclofenac and ketorolac (Tonussi and Ferreira, 1994, Granados-Soto et al., 1995, López-Muñoz et al., 1996), and some preferential cyclooxygenase-2 inhibitors, such as rofecoxib (Déciga-Campos and López-Muñoz, 2003, Déciga-Campos and López-Muñoz, 2004), were reported to involve activation of the l-arginine–NO–cyclic GMP pathway in addition to inhibition of prostaglandin synthesis.

On the basis of the above information, the present study was designed to investigate whether local activation of the NO–cGMP pathway is involved in the antinociceptive effect of indomethacin in the pain-induced functional impairment model in the rat (PIFIR model). The PIFIR model provides a model of inflammatory and chronic pain similar to that observed in clinical gout (López-Muñoz et al., 1993).

Section snippets

Animals

Female Wistar rats [Crl:(WI)BR] weighing 180–200 g were used in this study. Female animals were employed in order to establish a comparison with our previous data, which were obtained using female rats (Déciga-Campos and López-Muñoz, 2003, Déciga-Campos and López-Muñoz, 2004, López-Muñoz et al., 2004). The animals were housed in a temperature- and light-controlled room under a 12:12-h light/dark cycle (light on at 7:00 A.M.) with water and food provided ad libitum. Twelve hours before the

Antinociceptive effect of indomethacin

Oral administration of indomethacin produced a dose-dependent antinociceptive effect in the PIFIR model. At a dose of 5.6 mg/kg the drug induced an antinociceptive effect of 149.7±18.0 au. Since the maximum antinociceptive effect (AUC) that may be observed in the PIFIR model under the present experimental conditions is 375 au (López-Muñoz et al., 1993), the recovery of functionality produced by the above dose of indomethacin was 40% (data not shown). In order to investigate the role of the

Discussion

Indomethacin is a nonselective cyclooxygenase inhibitor, however, inhibition of prostaglandins synthesis does not completely explain indomethacin-induced antinociception. In this work, indomethacin-induced antinociception was blocked by the local administration of l-NAME, a nonselective inhibitor of the NO synthase. These results suggest that local NO release may play a role in the peripheral antinociceptive effect produced by indomethacin. A previous study from our laboratory reported that

Acknowledgements

We thank F. Sánchez, A. Huerta and L. Oliva for technical assistance.

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