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      Time Dependent Antinociceptive Effects of Morphine and Tramadol in the Hot Plate Test: Using Different Methods of Drug Administration in Female Rats

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          Abstract

          Morphine and tramadol which have analgesic effects can be administered acutely or chronically. This study tried to investigate the effect of these drugs at various times by using different methods of administration (intraperitoneal, oral, acute and chronic). Sixty adult female rats were divided into six groups. They received saline, morphine or tramadol (20 to 125 mg/Kg) daily for 15 days. A hot plate test was performed for the rats at the 1 st, 8 th and 15 th days. After drug withdrawal, the hot plate test was repeated at the 17 th, 19 th, and 22 nd days. There was a significant correlation between the day, drug, group, and their interaction (P<0.001). At 1 st day (d1), both morphine, and tramadol caused an increase in the hot plate time comparing to the saline groups (P<0.001), while there was no correlation between drug administration methods of morphine and/or tramadol. At the 8 th day (d8), morphine and tramadol led to the most powerful analgesic effect comparing to the other experimental days (P<0.001). At the 15 th day (d15), their effects diminished comparing to the d8. After drug withdrawal, analgesic effect of morphine, and tramadol disappeared. It can be concluded that the analgesic effect of morphine and tramadol increases with the repeated use of them. Thereafter, it may gradually decrease and reach to a level compatible to d1. The present data also indicated that although the analgesic effect of morphine and tramadol is dose-and-time dependent, but chronic exposure to them may not lead to altered nociceptive responses later in life.

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          The female rat reproductive cycle: a practical histological guide to staging.

          During preclinical investigations into the safety of drugs and chemicals, many are found to interfere with reproductive function in the female rat. This interference is commonly expressed as a change in normal morphology of the reproductive tract or a disturbance in the duration of particular phases of the estrous cycle. Such alterations can be recognized only if the pathologist has knowledge of the continuously changing histological appearance of the various components of the reproductive tract during the cycle and can accurately and consistently ascribe an individual tract to a particular phase of the cycle. Unfortunately, although comprehensive reports illustrating the normal appearance of the tract during the rat estrous cycle have been available over many years, they are generally somewhat ambiguous about distinct criteria for defining the end of one stage and the beginning of another. This detail is absolutely essential to achieve a consistent approach to staging the cycle. For the toxicologic pathologist, this report illustrates a pragmatic and practical approach to staging the estrous cycle in the rat based on personal experience and a review of the literature from the last century.
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            Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.

            Tramadol hydrochloride produced dose-related antinociception in mouse abdominal constriction [ED50 = 1.9 (1.2-2.6) mg/kg i.p.], hot-plate [48 degrees C, ED50 = 21.4 (18.4-25.3) mg/kg s.c.; 55 degrees C, ED50 = 33.1 (28.2-39.1) mg/kg s.c.] and tail-flick [ED50 = 22.8 (19.2-30.1) mg/kg s.c.] tests. Tramadol also displayed antinociceptive activity in the rat air-induced abdominal constriction [ED50 = 1.7 (0.7-3.2) mg/kg p.o.] and hot-plate [51 degrees C, ED50 = 19.5 (10.3-27.5) mg/kg i.p.] tests. The antinociceptive activity of tramadol in the mouse tail-flick test was completely antagonized by naloxone, suggesting an opioid mechanism of action. Consistent with this, tramadol bound with modest affinity to opioid mu receptors and with weak affinity to delta and kappa receptors, with Ki values of 2.1, 57.6 and 42.7 microM, respectively. The pA2 value for naloxone obtained with tramadol in the mouse tail-flick test was 7.76 and was not statistically different from that obtained with morphine (7.94). In CXBK mice, tramadol, like morphine, was devoid of antinociceptive activity after intracerebroventricular administration, suggesting that the opioid component of tramadol-induced antinociception is mediated by the mu-opioid receptor. In contrast to the mouse tail-flick test and unlike morphine or codeine, tramadol-induced antinociception in the mouse abdominal constriction, mouse hot-plate (48 degrees or 55 degrees C) or rat hot-plate tests was only partially antagonized by naloxone, implicating a nonopioid component. Further examination of the neurochemical profile of tramadol revealed that, unlike morphine, it also inhibited the uptake of norepinephrine (Ki = 0.79 microM) and serotonin (0.99 microM). The possibility that this additional activity contributes to the antinociceptive activity of tramadol was supported by the finding that systemically administered yohimbine or ritanserin blocked the antinociception produced by intrathecal administration of tramadol, but not morphine, in the rat tail-flick test. These results suggest that tramadol-induced antinociception is mediated by opioid (mu) and nonopioid (inhibition of monoamine uptake) mechanisms. This hypothesis is consistent with the clinical experience of a wide separation between analgesia and typical opioid side effects.
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              Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states.

              Tramadol is a centrally acting analgesic which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. It may be administered orally, rectally, intravenously or intramuscularly. In patients with moderate to severe postoperative pain, intravenous or intramuscular tramadol has generally proved to be of equivalent potency to pethidine (meperidine) and one-fifth as potent as nalbuphine. Intravenous tramadol 50 to 150mg was equivalent in analgesic efficacy to morphine 5 to 15mg in patients with moderate pain following surgery; however, when administered epidurally tramadol was one-thirtieth as potent as morphine. Tramadol has demonstrated efficacy in a few studies in the short term treatment of chronic pain of various origins. Orally administered tramadol was found to be an effective analgesic in step 2 of the World Health Organization's guidelines for the treatment of patients with cancer pain. Tramadol is well tolerated in short term use with dizziness, nausea, sedation, dry mouth and sweating being the principal adverse effects. Respiratory depression has been observed in only a few patients after tramadol infusion anaesthesia. When used for pain relief during childbirth, intravenously administered tramadol did not cause respiratory depression in neonates. The tolerance and dependence potential of tramadol during treatment for up to 6 months appears to be low, although the possibility of dependence with long term use cannot be entirely excluded. Thus, evidence to date of the analgesic effectiveness of tramadol combined with a low respiratory depressant effect and low dependence potential in short term use, suggests that the drug may become a useful alternative to the opioid analgesics currently available for the treatment of patients with moderately severe acute or chronic pain.
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                Author and article information

                Journal
                Iran J Pharm Res
                Iran J Pharm Res
                IJPR
                Iranian Journal of Pharmaceutical Research : IJPR
                Shaheed Beheshti University of Medical Sciences (Tehran, Iran )
                1735-0328
                1726-6890
                Winter 2015
                : 14
                : 1
                : 303-311
                Affiliations
                [a ] Department of Biology, Faculty of Sciences, University of Urmia, Iran.
                [b ] Neurophysiology Research Center, Urmia University of Medical Sciences, Iran.
                [c ] Department of Biology, Faculty of Sciences, University of Gorgan, Iran.
                [d ] Department of English Language, Urmia University of Medical Sciences, Urmia, Iran.
                Author notes
                [* ]saboory@umsu.ac.ir
                Article
                ijpr-14-303
                4277643
                67140c18-c492-45e1-ad5d-e38e9a6a02a9
                © 2015 by School of Pharmacy, Shaheed Beheshti University of Medical Sciences and Health Services

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : October 2013
                : May 2014
                Categories
                Original Article

                morphine,tramadol,antinociceptive,hot plate,rat
                morphine, tramadol, antinociceptive, hot plate, rat

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