Comparison of the Analgesic Activity of Antiparkinsonian Aminoadamantane Derivatives Amantadine and Hemantane

The efficacy of some aminoadamantane derivatives used as neurodegeneration treatments is due to their ability to block NMDA receptors. But this mechanism of pharmacological action can also produce analgesic activity. Analgesic properties of two aminoadamantanes, amantadine (20 mg/kg) and hemantane (20 mg/kg), which were uncompetitive NMDA receptor antagonists, were assessed in rodent models of pain induced by different pain stimuli (tail-flick test, acetic twitches test in mice and formalin test in rats). Additionally, the anti-inflammatory properties of hemantane and amantadine were evaluated in mice with acetic peritonitis and in rats with hind paw edema induced by formalin injection. The results of our study demonstrate that the analgesic activity of the 1-aminoadamantane amantadine differs from the 2-aminoadamantane hemantane. The analgesic activity of amantadine administered intraperitoneally was more pronounced in the case of acute thermal pain in mice compared to hemantane, and only amantadine had a significant analgesic effect on the acute early phase of formalin pain in rats induced by the effect of the algogen on the primary sensory afferents. Hemantane was more effective than amantadine for relieving pain produced by inflammation owing to its pronounced anti-inflammatory activity: only hemantane decreased the amount of acetic twitches in mice that received drugs orally and was effective in the tonic phase of formalin pain in rats.

Intrathecal MK-801 inhibits formalin-induced activation of spinal p38-MAPK in rats

BACKGROUND： p38 mitogen-activated protein kinase （MAPK） plays an instrumental role in signal transduction from the cell surface to the nucleus, while subcutaneous injection of formalin can induce increased activation of spinal p38 MAPK. However, the mechanisms underlying the formalin-induced activation of spinal p38 MAPK in rats are unclear. OBJECTIVE： To observe the effects of N-methyl-D-aspartic acid （NMDA） receptor antagonist MK-801 on the formalin-induced activation of spinal p38 MAPK in rats. DESIGN, TIME AND SETTING： This randomized grouping, controlled animal experiment was performed at the Department of Physiology and Neurobiology, Shanxi Medical University between May and November 2007. MATERIALS： Forty eight healthy, adult Wistar rats were randomly divided into two groups： formalin ＋ normal saline （n = 12） and formalin ＋ MK-801 （n = 36）. The formalin ＋ MK-801 group was further divided into three subgroups according to the dosage of MK-801 （10, 50, and 100 nmol/L, 12 rats for each subgroup） METHODS： Following anesthesia, polyethylene tubing filled with sterile normal saline was implanted into the subarachnoid cavity. On postoperative days 5-8, rats received a 15 minute perfusion of normal saline or MK-801 （10, 50, and 100 nmol/L） in the formalin ＋ normal saline and formalin ＋ MK-801 groups, respectively, followed by formalin injection for the induction of nociceptive behavior. MAIN OUTCOME MEASURES： Detection of total p38 MAPK and of phosphorylated p38 MAPK by western Blot analysis; observation of nociceptive behaviors in the 1 hour after formalin injection. RESULTS： Western Blot analysis revealed that injection of formalin had no effect on total p38 MAPK expression but resulted in increased phosphorylation of p38 MAPK in the spinal cord. This increase was apparent after 5 minutes, peaked at 20 minutes, and thereafter descended and reached control levels after 45 minutes. Pretreatment with MK-801 （10, 50, 100 nmol/L） resulted in a dose-dependent reduction of p38 MAPK phosphorylation in the spinal cord, 20 minutes after formalin injection. Injection of 50 and 100 nmol/L MK-801 produced a suppression of the first phase of nociceptive behaviors, and all three doses of MK-801 resulted in dose-dependent inhibition of the second phase of nociceptive behaviors. CONCLUSION： The NMDA receptor participates in formalin-induced activation of p38 MAPK in the rat spinal cord.