Preclinical comparison of antinociceptive effects between ibuprofen, diclofenac, naproxen, and acetaminophen on acid-stimulated body stretching and acid-depressed feeding behaviors in rats.

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient's and doctor's previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1-24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10-32 mg/kg), and naproxen (3.2-10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.

Preclinical assessment of tramadol abuse potential: Effects of acute and repeated tramadol on intracranial self-stimulation in rats.

BACKGROUND: Tramadol is a widely used analgesic that activates mu-opioid receptors (MOR) and inhibits serotonin and norepinephrine transporters. This mixed pharmacology may limit both its own abuse potential and its modulation of abuse potential of other MOR agonists. AIMS: This study used an intracranial self-stimulation (ICSS) procedure to compare abuse-related effects produced by acute or repeated treatment with tramadol or morphine in rats. Abuse potential in ICSS procedures is indicated by a drug-induced increase (or 'facilitation') of ICSS responding. METHODS: Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond on a lever for pulses of electrical brain stimulation. Tramadol effects were evaluated after acute administration (3.2-32 mg/kg) in the absence or presence of the opioid antagonist naltrexone, the CYP2D6 hepatic-enzyme inhibitor quinine or a combination of both. Additionally, both tramadol and morphine were also tested before and after repeated tramadol (32 mg/kg/day for six days) or repeated morphine (3.2 mg/kg/day for six days). RESULTS: Acute tramadol produced primarily ICSS rate-decreasing effects that were antagonised by naltrexone but not by quinine or naltrexone + quinine. Tramadol also produced little or no ICSS facilitation after repeated tramadol or repeated morphine, and repeated tramadol did not enhance ICSS facilitation by morphine. By contrast, morphine-induced ICSS facilitation was enhanced by repeated morphine treatment. CONCLUSIONS: These results suggest that tramadol has lower abuse potential than other abused MOR agonists and that repeated tramadol exposure produces relatively little enhancement of abuse potential of other MOR agonists.

Effects of combined swimming exercise and non-steroidal anti-inflammatory drugs on inflammatory nociception in rats.

Pain is a growing health problem with an increasing prevalence, and represents a large burden worldwide. Pain control can be achieved through pharmacological and non-pharmacological (such as exercise) interventions. The prolonged use of analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs), is accompanied by numerous side effects. No previous studies have examined whether exercise may enhance the analgesic effect of NSAIDs. In the present study, the effect of ibuprofen and swimming exercise on nociception threshold were investigated using a rat model of inflammatory pain. A prophylactic swimming protocol and a treatment swimming protocol were used. In the two protocols, nociception was induced by intraplantar injection of Complete Freund's Adjuvant. The authors hypothesized that swimming exercise may enhance ibuprofen-induced antinociception. In the control group, nociception lasted for 17 days, and ibuprofen produced an antinociceptive effect at a dose of 32 mg/kg. However, swimming exercise enhanced ibuprofen-induced antinociception in the two swimming protocols. Notably, ibuprofen produced a significant increase in the nociception threshold at a dose of 10 mg/kg in the prophylactic swimming group. In addition, the duration of inflammation did not exceed 8 days under either swimming protocol. In conclusion, the combination of ibuprofen and swimming exercise was effective in controlling nociception in a rat model of inflammatory pain. Based on these observations, the combined use of exercise and ibuprofen may be a viable intervention for the control of chronic pain, and may decrease the potential for drug-induced side effects.

Estrogen relaxes gastric muscle cells via a nitric oxide- and cyclic guanosine monophosphate-dependent mechanism: A sex-associated differential effect.

Various gastrointestinal (GI) disorders have a higher prevalence in women than in men. In addition, estrogen has been demonstrated to have an inhibitory effect on the contractility of GI smooth muscle. Although increased plasma estrogen levels have been implicated in GI disorders, the role of gastric estrogen receptor (ER) in these sex-specific differences remains to be fully elucidated. The present study was designed to investigate the sex-associated differences in the expression of the two ER isoforms, ERα and ERß, and the effect of estrogen on gastric muscle contraction via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Experiments were performed on single gastric smooth muscle cells (GSMCs) isolated from male and female Sprague Dawley rats. The effect of acetylcholine (ACh), a muscarinic agonist, on the contraction of GSMCs was measured via scanning micrometry in the presence or absence of 1 µM 17ß-estradiol (E2), an agonist to the majority of ERs, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), an ERα agonist, or diarylpropionitrile (DPN), an ERß agonist. The protein expression levels of ER subtypes in GSMCs were measured using a specifically designed ELISA. GSMCs from female rats had a higher expression of ERα and ERß protein compared with GSMCs from males. ACh induced less contraction in female that in male GSMCs. Pre-treatment of GSMCs with E2 reduced the contraction of GSMCs from both sexes, but to a greater extent in those from females. PPT and DPN inhibited ACh-induced contraction in GSMCs from females. Furthermore, E2 increased NO and cGMP levels in GSMCs from males and females; however, higher levels were measured in females. Of note, pre-incubation of female GSMCs with Nω-nitro-L-arginine, a NO synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylyl cyclase inhibitor, reduced the inhibitory effect of estrogen on GSMC contraction. In conclusion, estrogen relaxes GSMCs via an NO/cGMP-dependent mechanism, and the reduced contraction in GSMCs from females by estrogen may be associated with the sex-associated increased expression of ERα and ERß, and greater production of NO and cGMP, compared with that in GSMCs from males.