Antinociceptive and anti-allodynic effects of 3-alkynyl selenophene on different models of nociception in mice

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Abstract

In this study, antinociceptive and anti-hyperalgesic effects of 3-alkynyl selenophene (3-ASP) were evaluated in mice. Acute toxicity of 3-ASP (1–50 mg/kg, per oral) was investigated in mice. 3-ASP neither caused toxicity nor affects locomotor activity in the rota-rod test. 3-ASP did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities, urea and creatinine levels. 3-ASP caused a significant increase in tail-immersion and hot-plate response latencies time. 3-ASP inhibited early and late phases of nociception caused by intraplantar (i.pl.) injection of formalin. 3-ASP reduced nociception produced by i.pl. injection of glutamate, bradykinin, phorbol myristate acetate (PMA) and capsaicin in mice. Mechanical hyperalgesia induced by Freund's Complete Adjuvant (CFA) was attenuated by 3-ASP administration to mice (maximal inhibition of 42 ± 11%). The anti-hyperalgesic effect of 3-ASP was maintained for up to 6 h. The antinociceptive effect of 3-ASP was not abolished by naloxone (5 mg/kg), discarding the involvement of opioidergic mechanism in this effect. These results indicate that 3-ASP at a dose range of 5–50 mg/kg was especially potent and produced systemic anti-hyperalgesic and antinociceptive actions in mice.

Introduction

Chronic persistent pain impacts negatively on quality of life, affecting several aspects of health and well-being including relationships, cognitive abilities and the capacity to work (Rustøen et al., 2008). The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP Task Force on Taxonomy, 1994). Although there is an arsenal of effective and widely used analgesics, there is some concern regarding their safety and side-effects, making their clinical use problematic (Jage, 2005).

The nociception involves the activation of specific primary sensory neuron subpopulations that transmit the nociceptive information to the spinal cord from where it is relayed to supra spinal levels (Millan, 1999). Through the tissue damage may occur by activation of nociceptors through the release of several mediators, including excitatory amino acids, peptides, protons, lipids and cytokines, which bind to receptors and activate signaling pathways (Gilchrist et al., 1996). Thus, pain can be a subject to multiple levels of biochemical and pharmacological controls, involving a diversity of cell types and soluble mediators (Ji and Strichartz, 2004). As a result, compounds that present antinociceptive effect are of potential therapeutic interest for the treatment of human and animal pain.

Under this point of view, organoselenium chemistry is a very broad and exciting field, with many opportunities for research and development of applications. Organoselenium compounds have become attractive synthetic targets because of their chemo-, regio-, and stereo-selective reactions, and their useful biological activities (Alves et al., 2008). These compounds have been reported as neuroprotective, antiulcer, cytoprotective, chemopreventive, antidepressant, anti-inflammatory and antinociceptive agents (Sies, 1993, Schewe, 1995; Yamagushi et al., Yamagushi et al., 1998, Combs and Gray, 1998, Nogueira et al., 2004). They have been also successfully utilized in haloperidol-induced orofacial dyskinesia (Burger et al., 2006) and apomorphine-induced stereotypy in mice (Machado et al., 2006).

The antinociceptive properties of organoselenium compounds, which could be relevant drugs for the management of pain, have been reported by our research group (Savegnago et al., 2007a, Savegnago et al., 2007b, Savegnago et al., 2007c, Jesse et al., 2008a, Jesse et al., 2008b, Pinto et al., 2008). In fact, diphenyl diselenide (PhSe)2, a simple diaryl diselenide, attenuates chemical-induced nociception, including visceral pain induced by acetic acid, licking behavior induced by intraplantar injection of glutamate, formalin, capsaicin, bradykinin and phorbol 12-myristate 13-acetate (PMA) in mice (Nogueira et al., 2003, Zasso et al., 2005, Savegnago et al., 2007b). Recently, bis-selenide alkene derivatives were demonstrated to produce antinociception when assessed in acetic acid, capsaicin and tail-immersion behavioral tests and this effect is not influenced by opioidergic mechanism (Savegnago et al., 2006).

In addition to organoselenium compounds described above, chalcogenophenes are compounds widely studied (Hudson et al., 1989, Gonçales et al., 2005, Meotti et al., 2004, Wilhelm et al., 2009a, Wilhelm et al., 2009b). Among chalcogenophenes, selenophenes play an important role in organic synthesis because of their electrical properties and stability (Alves et al., 2008). Besides, in previous studies we demonstrated that 3-alkynyl selenophene (3-ASP), the selenophene studied in this paper, presents anticonvulsant and antioxidant effects in 21-day-old rats in a pilocarpine model of seizures. This study confirmed the anticonvulsant activity of 3-ASP and the drug's ability in reducing the oxidative stress in the pilocarpine model (Wilhelm et al., 2009a). 3-ASP has hepatoprotective effect against acute liver injury induced by D-galactosamine and lipopolysaccharide in rats by the mechanism that involves its antioxidant activity (Wilhelm et al., 2009b).

Based on the results described here, the aims of the present study were to evaluate: (i) the antinociceptive effect of 3-ASP on different models of acute nociception; (ii) the possible involvement of opiod system in 3-ASP antinociceptive effect; and (iii) the anti-hyperalgesic effect of 3-ASP in mechanical hyperalgesia induced by Freund's Complete Adjuvant in mice.

Section snippets

Drugs

3-alkynyl selenophene (1-(2,5-diphenylselenophen-3-yl)-3-methylpent-1-yn-3-ol; 3-ASP; Fig. 1) was prepared according to the literature method (Alves et al., 2008). Analysis of the 1H NMR and 13C NMR spectra showed analytical and spectroscopic data in full agreement with its assigned structure. The chemical purity of 3-ASP (99.9%) was determined by GC/HPLC. 3-ASP was dissolved in canola oil and administered by intragastric gavage as a single oral dose (p.o.). All other drugs were dissolved in a

Effect of 3-ASP on nociception in mice

Fig. 2A and B show that 3-ASP caused significant inhibition of both early (0–5 min) and late (15–30 min) phases of formalin-induced licking. The maximal inhibition values observed were 41 ± 10% and 46 ± 4% for the first and second phases, respectively.

3-ASP (10–50 mg/kg) caused an inhibition of the capsaicin-induced licking response (Fig. 3A), with a maximal inhibition value of 71 ± 7%. As can be seen in Fig. 3B, 3-ASP (5–50 mg/kg, p.o.) significantly inhibited nociception induced by i.pl. injection

Discussion

The present study demonstrates that 3-ASP administered orally did not produce acute toxicity and induced antinociception in chemical and thermal models of nociception in mice, without modifying the locomotor activity of mice in the rota-rod test.

We have found that 3-ASP decreased the nociception in both phases of the formalin test, with a greater potency in the inflammatory phase. Morphine (Shibata et al., 1989) and non-steroidal anti-inflammatory drugs (NSAIDs) (Martindale et al., 2001)

Acknowledgements

The financial support by UFSM, FAPERGS, CAPES and CNPq is gratefully acknowledged.

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