Model Of Loperamode-Induced Hyperalgesic Priming In Rats

E. Shekunova(3), A. Malyshkin(3), V. Kashkin(1–3) 1-Valdman Institute of Pharmacology, Pavlov First St. Petersburg State Medical University Saint Petersburg, 6–8, L’va Tolstogo str., 197022, Russia; 2-Sechenov Institute of Evolutionary Physiology and Biochemistry St. Petersburg, 44 Morisa Toreza str., 194223, Russia; 3-Institute of experimental pharmacology Kuzmolovskiy, Vsevolozhskiy district, Leningrad region, Zavodskaya, b. 245, 3, st. 188663, Russia; Е-mail: kashkinv@doclinika.ru

Abstract

The aim of this study was to develop a model for the development of hyperalgesic priming using loperamide in rats. It is known that the three subsequent intradermal injections of the selective µ-opioid receptor agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandins E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. Hyperalgesic priming is considered as a model of the transition of from acute to chronic pain. In this study, three subplantar injections of loperamide (2 μg per animal) were used to induce a prolonged hyperalgesic condition. Repeated administration of loperamide was performed at an interval of 1 hour. PGE2 was injected subplantar at a dose of 5 μg per animal one hour after the last injection of loperamide. Pain sensitivity was estimated by the level of thresholds of paw-withdrawal reflex to mechanical stimuli which applies to the plantar surface of the rat’s hindpaw. It has been shown that three subsequent loperamide injections (in contrast to a single administration) do not have an analgesic effect on the nociceptive reaction induced by PGE2. It could be consider as development of acute tolerance to the analgesic effect of loperamide. In addition, repeated administration of loperamide led to the development of a long-term hyperalgesia condition after the administration of PGE2, suggesting the development of hyperalgesic priming. Unlike priming caused by an inflammatory agent, such as carrageenan, which requires 3–5 days to develop, priming caused by loperamide manifests within a few hours after the last injection of loperamide. Thus, this method can be used for development of pharmacological agents that may restore the sensitivity to opiates, which is important for pain management.

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