Antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole. A Celecoxib structural analog in models of pathological pain

doi:10.1016/j.pbb.2014.07.005

Pharmacology Biochemistry and Behavior

Volume 124, September 2014, Pages 396-404

https://doi.org/10.1016/j.pbb.2014.07.005 Get rights and content

Highlights

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FTosPz prevents and reduces the mechanical hyperalgesia in a postoperative model.
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FTosPz reduces the hyperalgesia, but not the edema in an arthritis model.
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FTosPz reduces the mechanical hyperalgesia in a neuropathic pain model.
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FTosPz did not alter the AST/ALT enzyme activities or urea/creatinine levels.
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FTosPz did not alter the COX-1 and COX-2 enzyme activities.

Abstract

Pain is the most common complaint in the medical field and the identification of novel compounds that can effectively treat painful states without causing side effects remains a major challenge in biomedical research. The aim of the present study is to investigate the antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (FTosPz) in models of pathological pain in mice and compare these effects with those produced by Celecoxib. FTosPz (100–500 μmol/kg) or Celecoxib (26–260 μmol/kg) was administrated orally. The administration of either FTosPz or Celecoxib reduced the hyperalgesia but not the edema or leukocyte infiltration that was caused by Complete Freund's Adjuvant (CFA), used as an arthritis model. Oral administration of both FTosPz and Celecoxib also attenuated the postoperative hyperalgesia as well as the hyperalgesia caused by partial sciatic nerve ligation, used as a neuropathic pain model. FTosPz and Celecoxib produced antinociceptive effects without altering the locomotor activity of animals. Furthermore, FTosPz neither altered AST/ALT enzyme activity nor the urea/creatinine levels. Still, the FTosPz did not alter the COX-1 and COX-2 enzyme activities. Thus, FTosPz is an interesting prototype for the development of novel analgesic drugs.

Graphical abstract

Introduction

Pain is the most common complaint in the medical field, dominating and disrupting the quality of life of many patients. However, the arsenal of effective and safe analgesics is still relatively small (Williams et al., 1999, Woller and Hook, 2013). Many of the currently available pharmacological treatments to alleviate pain (especially nonsteroidal anti-inflammatory drugs and opioids) are only partially effective and may be accompanied by distressing side effects or have abuse potential (Chan, 2006, Graziottin et al., 2011, Scholz and Woolf, 2002).

Mechanical hyperalgesia is an increased pain sensitivity which can be produced by mechanical stimuli and is characteristic of pathological pain. Both joint inflammation and surgical procedures are important causes of pathological inflammatory pain sensitivity to mechanical stimulus. In arthritis, the joint nerves become sensitized, producing acute and chronic pain (von Banchet et al., 2007). The current therapies to alleviate joint pain have limited effectiveness and certain drugs produce unwanted negative side effects, thereby precluding their long-term use (McDougall, 2006). Moreover, in postoperative pain, approximately half of all patients experience moderate to severe pain after surgery (Pogatzki-Zahn et al., 2007) and the treatments used to treat it cause side effects that often limit their use (Mercadante, 1999). In addition, the pain related with the injury to peripheral nerves often results in a persistent neuropathic pain (Malmberg and Basbaum, 1998, Woolf and Mannion, 1999). Neuropathic pain is a major challenge in clinical medicine because it is largely resistant to the currently available analgesics (Dworkin et al., 2007, Woolf and Mannion, 1999). The identification of compounds that can more effectively and safely treat both acute and chronic pain states and, additionally, show a reduced tendency to cause the side effects associated thereof, remains a major unmet challenge in biomedical research.

In this context, pyrazole and its derivatives bearing a diversity of functional groups have attracted a great deal of 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 and Goto, 2000). In recent years, we have synthesized new pyrazole derivatives and reported their antinociceptive and antipyretic effects in animal models of inflammation, fever, and pain (Milano et al., 2008a, Milano et al., 2008b, Prokopp et al., 2006, Sauzem et al., 2007, Souza et al., 2001, Tomazetti et al., 2005). We have previously demonstrated that 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (FTosPz) reduced the inflammatory pain induced by carrageenan and the visceral nociception induced by acetic acid. Furthermore, FTosPz causes neither motor impairment nor gastric ulcer or hypothermia in animals (Oliveira et al., 2009). However, the pain models used to evaluate the antinociceptive effect of FTosPz have been considered not clinically relevant.

Taking this into account, the purpose of the present study was to investigate the effects of FTosPz in three pathological pain models that afflict millions of people worldwide. These models are the arthritic pain caused by CFA, the postoperative pain induced by surgical incision, and the neuropathic pain induced by partial ligation of the right sciatic nerve.

Section snippets

Animals

Male Swiss mice (25–35 g) were kept in a temperature-controlled room (22 ± 2 °C) under a 12 h light–dark cycle (lights on from 6:00 a.m. to 6 p.m.) with standard lab chow and tap water ad libitum. Animals were acclimatized to the laboratory for at least 2 h before the experiments and were used only once. All of the experiments were carried out between 8:00 a.m. and 5:00 p.m. The data reported in this study were carried out in accordance with current ethical guidelines for the investigation of

Effects of FTosPz or Celecoxib on the incisional pain model

In this model, we evaluated the preemptive and curative antinociceptive effects of FTosPz and Celecoxib in the postoperative pain model. The plantar incision produced a marked hyperalgesia in the injured paw at all of the time points measured (0.5–6 h) in vehicle treated mice when compared with the baseline (B) [F(2,16) = 32.93, P < 0.001]. The pretreatment with FTosPz or Celecoxib significantly decreased hyperalgesia at 1 and 2 h [F(8,64) = 3.6, P < 0.01] after the treatments (Fig. 2A). FTosPz or

Discussion

Pathological painful states are difficult to treat and pain is the most common complaint in the medical field; it produces severe distress for many patients, dominating and disrupting the quality of their lives (Kloppenburg and Kwok, 2011, Woller and Hook, 2013). However, the arsenal of effective and safe analgesics is still relatively small (Scholz and Woolf, 2002, Williams et al., 1999). Despite the grant advances in the last decade, the discovery and development of a safe, effective, and

Acknowledgments

This study was supported by the Programa de Apoio aos Núcleos de Excelência (PRONEX) (Grant Nº 0408660) (Brazil). We also acknowledge fellowships from Conselho Nacional de Desenvolvimento Científico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES).

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Although there are many treatment options available, many of them are only partially effective or are associated with adverse side effects and potential for drug abuse and addiction [4,5]. Based on this scenario, our research group has concentrated efforts in the search for new bioactive molecules from natural products, effective in the treatment of acute and chronic painful [6–8]. Natural products are considered important sources of investigation of potential new drugs, and studies of bioactive molecules effective in the treatment of acute and chronic pain conditions are promising [9–11].
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Antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole. A Celecoxib structural analog in models of pathological pain

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Animals

Effects of FTosPz or Celecoxib on the incisional pain model

Discussion

Acknowledgments

Pain

Lancet

Bioorg Med Chem

J Fluor Chem

J Neurosci Methods

Am J Med

Pain

Neuropharmacology

Neuropharmacology

Eur J Med Chem

Pain

Reg Anesth Pain Med

Neuroscience

Neuroscience

Neurosci Lett

Behav Brain Res

Pharmacol Biochem Behav

Biochem Pharmacol

Pain

Pain

Eur J Pharmacol

Life Sci

Neurosci Lett

Eur J Pharmacol

Best Pract Res Clin Anaesthesiol

Eur J Pharmacol

Gastroenterol Clin North Am

Br J Anaesth

Anal Biochem

Pain

Neuroscience

J Neurosci Methods

Neuropharmacology

Clin Liver Dis

Eur J Pharmacol

Exp Neurol

Lancet