Ketoprofen and antinociception in hypo-oestrogenic Wistar rats fed on a high sucrose diet

Abstract

Non-steroidal anti-inflammatory drugs such as ketoprofen are the most commonly used analgesics for the treatment of pain. However, no studies have evaluated the analgesic response to ketoprofen in conditions of obesity. The aim of this study was to analyse the time course of nociceptive pain in Wistar rats with and without hypo-oestrogenism on a high sucrose diet and to compare the antinociceptive response using ketoprofen. Hypo-oestrogenic and naïve rats received a hyper caloric diet (30% sucrose) or water ad libitum for 17 weeks, the thermal nociception (“plantar test” method) and body weight were tested during this period. A biphasic response was observed: thermal latency decreased in the 4th week (hyperalgesia), while from 12th to 17th week, thermal latency increased (hypoalgesia) in hypo-oestrogenic rats fed with high sucrose diet compared with the hypo-oestrogenic control group. At 4th and 17th weeks, different doses of ketoprofen (1.8–100 mg/kg p.o.), were evaluated in all groups. The administration of ketoprofen at 4th and 17th weeks showed dose-dependent effects in the all groups; however, a greater pharmacological efficacy was observed in the 4th week in the hypo-oestrogenic animals that received sucrose. Nevertheless, in all the groups significantly diminish the antinociceptive effects in the 17th week. Our data showed that nociception was altered in the hypo-oestrogenic animals that were fed sucrose (hyperalgesia and hypoalgesia). Ketoprofen showed a dose-dependent antinociceptive effect at both time points. However, hypo-oestrogenism plus high-sucrose diet modifies the antinociceptive effect of ketoprofen.

Introduction

Pain is a condition that affects thousands of people in the world. However, it has been shown that individuals with increased body weight are more likely to have problems with pain (Marcus, 2004, Wilson et al., 2010). Controversies exist regarding the perception of pain in obese subjects. Some studies report a hyperalgesic state associated with obesity (Roane and Martin, 1990, Sugimoto et al., 2008, Buchenauer et al., 2009), while others have proposed the existence of hypoalgesic processes (Ramzan et al., 1993, Zhang et al., 1994, Sugimoto et al., 2008). Moreover, the most frequent cases that have been documented clinically in obese people involve back pain (Hitt et al., 2007; D’Arcy, 2011) and arthritis pain (Marcus, 2004), triggered mainly due to a mechanical effect on the joints by weight gain. Obesity has also been associated with other chronic pain conditions, such as migraine and headache (Goadsby et al., 2002, Rossi et al., 2013). For this reason, it is common for these patients to be treated with analgesic drugs. The most widespread drug therapy currently used to relieve nociceptive and inflammatory pain involves the non-steroidal anti-inflammatory analgesics (NSAIDs) and opioids (Ong et al., 2007). NSAIDs are the most widely prescribed drugs in clinical medicine; they are heterogeneous substances with varying nonsteroidal chemical structures (Laine, 2001). This group of drugs, which are indicated in the treatment of acute and chronic pain (Whiteside et al., 2004, Ong et al., 2007), is characterized by analgesic anti-inflammatory and antipyretic properties (Dworkin y Gitlin, 1991). Ketoprofen is a member of this group. As other NSAIDs, ketoprofen exerts its analgesic effect through at least three mechanisms of action, clearly identified as: 1) inhibition of prostaglandin synthesis (Avouac and Teule, 1988, Kubota et al., 1997), 2) interaction with the serotonergic system (Díaz-Reval et al., 2001, Díaz-Reval et al., 2004) and 3) inhibition of proinflammatory cytokines (Choi et al., 2013). Preclinical studies have indicated that ketoprofen exhibits dose-dependent effects in different models of acute and inflammatory pain (Díaz-Reval et al., 2001, Díaz-Reval et al., 2004, Aguilar-Carrasco et al., 2014). However, no studies have evaluated the analgesic response of ketoprofen in conditions where there is an increase in body weight; therefore, the antinociceptive effect it may have under these conditions is unknown. The effects may differ because pathological conditions can change the activity of drugs, mainly through pharmacokinetic and/or pharmacodynamic alterations (Lloret et al., 2009).

Therefore, the objectives of this study were to evaluate nociception in hypo-oestrogenic and naïve female Wistar rats under conditions of increasing weight up to a state of obesity achieved through the provision of a high sucrose diet (30% in drinking water) and to analyse the antinociceptive response to ketoprofen.