Week off Two days’ Model on Analgesic Efficacy of Chronic Administration of Morphine in Mice
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 6, Issue 5
Abstract
Morphine is an important analgesic pain control for the patients. The unwanted morphine analgesic tolerance limited its using. In this study, we attempted to improve the effectiveness of morphine and delayed morphine tolerance by intermittent administrations of morphine. Moreover, we have designed a new composite for management of pain, e.g. combination (GTPm) of green tea polyphenols (GTP, 30 mg/kg/day) with memantine (3mg/kg/day). The results showed that morphine (I.P. injection, 10 mg/kg/day) treated mice received morphine for consecutive five days followed by two days’ off can maintain analgesic tail flick test after long-term (54 days) administration of morphine. The hot plate analgesic test showed that GTPm enhanced analgesic effects of morphine (10mg/kg) but not with the higher doses of morphine (15 mg/kg and 30mg/kg), suggesting that GTPm has a biphasic influence on morphine analgesic effects in hot plate test. Moreover, capsaicin-induced orofacial pain test showed that GTPm also enhanced morphine analgesic effects even as long as at day 102th. The mice at this stage of chronic prolonged administration of morphine have revealed behavioral changes by markedly increased in locomotor and jump activities and decreased in rest time. The mechanism behind this prolonged antinociceptic efficacies of morphine in capsaicin-induced orofacial pain required further investigation. In conclusion, week off two days model of morphine administration attenuated morphine tolerance in tail flick pain test and capsaicin induced orofacial-pain in mice. The clinical treatment for pain control such as terminal cancer patients is important to improve the quality of life. Morphine is one of the most commonly used analgesics for those patients needed severe pain control [1]. However, along with morphine analgesic effects, it caused severe unwanted effects too (morphine tolerance and addiction). These side effects of morphine may hinder both the physician and the patient from using it. It is urgent to explore a novel regimen with more effective and less side effects for clinical application of morphine. Morphine acts directly on the central nervous system (CNS) to decrease the pain sensation [2,3]. However, morphine is known a highly addictive substance and the development of tolerance to morphine is also well known. Several hypotheses are given about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects). CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine. Recently, studies claimed that neuroinflammation and the oxidative stress (increased production of reactive oxygen radicals (ROS), nitric oxide (NO) and peroxynitrite) [4-6] as well as activation of glutamate NMDA receptor played important roles in the generation of morphine tolerance and addiction [7,8]. In this study, we attempted to improve the effectiveness of morphine and delayed the development of morphine analgesic tolerance by a low dose and intermittent administration of morphine. Furthermore, we designed a new composite (GTPm) of combination of green tea polyphenols (GTP) with memantine. GTPs possessed antioxidant, anti-inflammatory and neuroprotective effects [9-13] which exhibited synergistic effects with memantine (an antagonist of NMDA receptor) against neuronal excitotoxicity [14]. Thus, we have investigated effects of GTPm on morphine analgesic effects in tail flick thermal pain test, hot plate paw withdrawal test and the capsaicin-induced orofacial pain test. The results obtained indicated that week off two days model of morphine administration attenuated development of morphine tolerance.
Authors and Affiliations
Shoei-Yn Lin-Shiau, Hsi-Hsien Chou
Keywords
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- EP ID EP585836
- DOI 10.26717/BJSTR.2018.06.001426
- Views 142
- Downloads 0
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