Elsevier

Life Sciences

Volume 83, Issues 21–22, 21 November 2008, Pages 739-746
Life Sciences

Antinociceptive action of 4-methyl-5-trifluoromethyl-5-hydroxy-4, 5-dihydro-1H-pyrazole methyl ester in models of inflammatory pain in mice

https://doi.org/10.1016/j.lfs.2008.09.010Get rights and content

Abstract

Aims

The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4).

Main methods

The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice.

Key findings

MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66 ± 7%, 73 ± 9% and 88 ± 8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53 ± 9%, 83 ± 7% and 84 ± 7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity.

Significance

The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.

Introduction

The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic (Julius and Basbaum, 2001). While physiological pain requires intense but not damaging stimuli and is typically transient and well localized, pathological pain causes alterations in the somatosensory system, amplifying responses and increasing sensitivity to peripheral stimuli so that pain can be activated by normally innocuous stimuli (allodynia) (Woolf and Costigan, 1999). It is now well recognized that persistent pain resulting from peripheral inflammation associated with tissue damage causes the release of multiple nociceptive mediators, resulting in increased long-lasting discharge of primary sensory fibres (Besson, 1999, Julius and Basbaum, 2001).

One important and prevalent cause of pain is related with joint inflammation. In arthritis, joint nerves become sensitized, producing chronic or episodic pain. Current therapies to help alleviate joint pain have limited effectiveness and certain drugs produce unwanted negative side effects, thereby precluding their long-term use (McDougall, 2006). Another common cause of inflammatory pain is postoperative pain, which is a unique form of acute pain (Brennan et al., 1996, Zahn et al., 2005). Unfortunately, acute postoperative pain control seems not to have substantially improved over the last decade or so (Apfelbaum et al., 2003). In this context, in addition to opioids, the non-steroidal anti-inflammatory drugs (NSAIDS) are probably the most widely used drugs in clinics for pain treatment (Scholz and Woolf, 2002). In spite of their proved efficacy, both types of drugs produce unwanted side effects that limit their use (Kromer, 1988, Mercadante, 1999). Among NSAIDS, the pyrazole-derived drug dipyrone is a good alternative due to its high efficacy, low cost and good gastric tolerability (Camu and Vanlersberghe, 2002).

Pyrazole compounds have attracted a great deal of research interest due to their wide range of pharmacological properties (Bekhit and Abdel-Azien, 2004, Cheng et al., 1986), mainly antinociceptive activities (Gürsoy et al., 2000, Matheus et al., 1991, Ochi et al., 1999a, Ochi et al., 1999b). MPF4 is a novel pyrazole derivative discovered by screening compounds containing a pyrazole scaffold to find new antinociceptive drugs (De Souza et al., 2001, Godoy et al., 2004, Tabarelli et al., 2004, Prokopp et al., 2006, Sauzem et al., 2008). Recently, it was reported that MPF4 presented antinociceptive effects in formalin and hot-plate tests with efficacies similar to dipyrone or morphine (Milano et al., 2008). The antinociceptive effect of MPF4 was reversed by the opioid receptor antagonist, naloxone, but not by the alpha2-adrenergic receptor antagonist, yohimbine, nor by pre-treatment with the serotonin synthesis inhibitor, p-chlorophenylalanine ethyl ester. Furthermore, MPF4 was less effective than morphine to reduce gastrointestinal transit. In contrast to morphine, MPF4 did not generate a tolerance to its antinociceptive effect and did not present cross-tolerance with morphine (Milano et al., 2008). Thus, the effects of MPF4 are different from the reference pyrazole analgesic drug dipyrone since it has been demonstrated that dipyrone may produce tolerance as well as cross-tolerance with morphine (Tortorici and Vanegas, 2000). Thus, MPF4 produces antinociceptive action by stimulating the opioid system, but presents fewer side effects than morphine or dipyrone.

Therefore, the present study was designed to investigate whether MPF4 exhibits anti-allodynic effects in two models of pain, arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice. Furthermore, we have investigated the role of opioid receptors in the anti-allodynic action produced by MPF4. Finally, we have compared the antinociceptive effect of MPF4 with that produced by dipyrone and morphine and assessed the effects of MPF4 on motor function and gastric integrity.

Section snippets

Animals

Three-month-old male albino Swiss mice (30–40 g) bred in our animal house were used. The animals were housed at controlled temperature (22 ± 2 °C) with a 12 h light/dark cycle and with standard lab chow and tap water ad libitum. The animals were habituated to the experimental room for at least 2 h before the experiments. The experiments reported in this study were carried out in accordance with current ethical guidelines for the investigation of experimental pain in conscious animals (Zimmermann,

Effects of MPF4 on mechanical allodynia and paw edema induced by CFA injection

CFA produced marked mechanical allodynia [F(5,95) = 10.92, P < 0.001] and paw edema [F(2,38) = 33.34, P < 0.001] 48 h after i.pl. injection. The intraperitoneal administration of MPF4 (1.0 mmol/kg, i.p) reduced mechanical allodynia induced by CFA for up to 4 h after its administration [F(5,95) = 8.94, P < 0.001] (Fig. 1A). The maximal effect was observed 1 h after administration with an inhibition of 94 ± 7%. However, MPF4 (1.0 mmol/kg, i.p) failed to reduce paw edema produced by CFA, when measured 3 h after

Discussion

We have previously demonstrated that MPF4 given intraperitoneally decreases neurogenic and inflammatory phases of nociception in the formalin test and also produces a dose-dependent antinociception in the hot-plate test without causing motor impairment (Milano et al., 2008). In addition, the antinociceptive effect of MPF4 was reversed by the opioid receptor antagonist, naloxone. Moreover, MPF4 given daily did not generate a tolerance to its antinociceptive effect or cross-tolerance with

Acknowledgments

This study was supported by the Conselho Nacional de Desenvolvimento Científico (CNPq), by the Financiadora de Estudos e Projetos (FINEP), by the Programa de Apoio aos Núcleos de Excelência (PRONEX) and by the Fundação de Amparo à pesquisa do Estado do Rio Grande do Sul (FAPERGS) (Brazil). The fellowships from CNPq, CAPES and FAPERGS are also acknowledged.

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