European journal of pharmacology
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Combination of two or more analgesics is widely used for the treatment of moderate and severe pain syndromes, allowing usage of lower doses of each compound and thereby limiting side effects; there is currently a large interest in investigating the potential advantages of combinations between opioids and non-steroidal inflammatory drugs (NSAIDs), coxibs in particular. The rat orofacial formalin test is a useful pre-clinical model of inflammatory trigeminal pain for evaluating antinociceptive activity of analgesics and their combinations. Injection of formalin in the rat wiskerpad induces a stereotyped response (rubbing), consisting of two distinct phases: a first 'phasic' phase and a second 'tonic' phase. ⋯ We observed a statistical difference between the theoretical and the experimental ED(50), which indicated synergistic interaction in the second phase. Concerning the first phase, we assumed that the antinociceptive effects were almost completely to be attributed to buprenorphine, since lumiracoxib was ineffective when administered alone. However, we found an unexpected difference between the theoretical and experimental ED(50), suggesting synergism in the first phase as well.
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The formalin test is used as a primary behavioural screen for assaying the antinociceptive activity of compounds in laboratory rodents. After hindpaw formalin injection, nociceptive behaviours are expressed in a biphasic pattern and correlate closely with the concentration of formalin injected. Here, the antinociceptive efficacy of six compounds used in the clinical treatment of chronic pain was compared in rats injected with either 1% or 5% formalin. ⋯ However second phase nociception was only attenuated in 5% formalin-injected rats giving rise to a 6 fold increase in potency compared with 1% formalin-injected rats. The micro-opioid receptor agonist morphine (1-6 mg/kg) and the combined micro-opioid receptor agonist/monoamine reuptake inhibitor tramadol (5-50 mg/kg) both attenuated nociceptive behaviours throughout the duration of both the 1% and 5% tests; no difference in antinociceptive potency occurred for either compound during second phase. Thus, for mechanistically-distinct compounds the predictive antinociceptive capacity of the formalin test can vary with the concentration of formalin injected, likely as a result of peripheral and central nociceptive signalling mechanisms being differentially engaged.
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A major symptom of persistent neuropathic pain, which may develop after peripheral nerve injury, is hypersensitivity (allodynia) to normally innocuous cold stimuli. Although the anticonvulsant pregabalin has been demonstrated to relieve neuropathic pain, both in preclinical models and clinically, the analgesic effect of the drug in animals has not been profiled for cold hypersensitivity. Therefore, we examined the effect of pregabalin (single oral dosing: 30, 100, 300 micromol/kg) on cold allodynia in two models of chronic neuropathic pain, the spared nerve injury (SNI) and the spinal nerve ligation (SNL) models. ⋯ For comparison, only the highest dose tested of pregabalin (300 micromol/kg), significantly decreased pain responses in phase 2 of the rat formalin test (approximately 67% pain inhibition). However, pregabalin at this high dose also affected other centrally mediated behavioural functions, such as motor activity and anxiolytic behaviour in naïve animals, which could potentially interfere with the pain readout. The present study demonstrates that oral administration of pregabalin significantly reduces both cold allodynia induced in the SNI and the SNL models of neuropathic pain as well as formalin-induced nociception, albeit with different sensitivity and potency.
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Propofol, a short-acting intravenous anaesthetic agent has gained wide acceptance since its introduction in the late 80s, not only in operating rooms but also in other departments, due to its several advantages. Apart from its multiple anaesthetic advantages, it has been reported recently that propofol exerts a number of non-anaesthetic effects. The drug stimulates constitutive nitric oxide (NO) production and inhibits inducible NO production. ⋯ Moreover, it has antioxidant, immunomodulatory, analgesic, antiemetic and neuroprotective effects. Furthermore, propofol inhibits both platelet aggregation and intracellular calcium increases in response to thrombin or ADP and it also exerts direct inhibitory effects on recombinant cardiac sarcolemmal KATP channels. All these beneficial properties may expand propofol's clinical use.
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Ghrelin, the natural ligand of the growth hormone secretagogue receptor (ghrelin receptor), is an orexigenic gut hormone with prokinetic action in the upper gastrointestinal tract. Previously we have shown in a rodent model of postoperative ileus that the synthetic ghrelin receptor agonist TZP-101 prevents the delay in gastric emptying and improves small intestinal transit. The goal of the present study was to investigate whether TZP-101 affects colonic transit and food intake in rats with postoperative ileus. ⋯ TZP-101 (0.03-1 mg/kg) dose-dependently decreased the time to first bowel movement and increased fecal pellet output measured at 12 h and 24 h post-surgery compared to the vehicle. The administration of TZP-101 was not associated with a significant alteration in food intake. In conclusion, this study provides the first experimental evidence that a novel ghrelin receptor agonist improves large bowel function in rats with postoperative ileus, suggesting that TZP-101 may be useful in the clinic to accelerate upper gastrointestinal transit and to shorten the time to the first bowel movement following surgery.