Effect of Spinally Administered Simvastatin on the Formalin-Induced Nociceptive Response in Mice

Abstract

Statins are widely prescribed for treatment of hyperlipidemia. Statins lower plasma cholesterol levels through the inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase. Several large clinical trials indicated that statins reduce the morbidity and mortality of coronary artery disease and the incidence of stroke (1). These pleiotropic effects of statins are considered to result from their actions other than lipid lowering, since the overall clinical benefits of statin therapy appeared to be greater than what might be expected from the lipid lowering effect (2). Indeed, another lipid lowering compound, ezetimibe, that inhibits intestinal cholesterol absorption did not show pleiotropic effects in humans (3).It was reported that statins showed antinociceptive and antihyperalgesic effects in mice and rats (4, 5). Simvastatin and rosuvastatin systemic treatment also attenuated thermal hyperalgesia and mechanical allodynia in sciatic nerve-ligated rats (6). These effects of statins have been considered to result from their anti-inflammatory actions. Recently, we observed that spinal activation of the mevalonate pathway induced the thermal hyperalgesia through the activation of spinal RhoA/Rho kinase signaling (7). Therefore, it can be speculated that the statinsinduced antinociception and antihyperalgesia is mediated by the inhibition of the mevalonate pathway in the central nervous systems. The present study was undertaken to define the action site of the highly lipophilic statin simvastatin on the formalin-induced nociceptive response in the mouse.The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals, Kyushu University of Health and Welfare, as adopted by the Committee on Animal Research of Kyushu University of Health and Welfare, which is accredited by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.Male ICR mice (Kyudo Laboratory Animals, Inc., Saga), weighing 20 -30 g, were used in this study. Animals were housed five per cage in a room maintained at 23°C ± 0.5°C with an alternating 12-h light-dark cycle. Food and water were available ad libitum. Animals were used only once in all experiments.The formalin test was performed according to the method described previously (7). After a 10-min acclimation period to individual observation cages, 25 μl of a 1.5% formalin solution was injected subcutaneously into , 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan Received January 6, 2012; Accepted March 12, 2012 Abstract. Clinical and experimental observations indicated that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor statins have pleiotropic effects. The present study determined the antinociceptive property of centrally administered simvastatin on the formalin-induced nociception in the mouse. Intrathecal administration of simvastatin at doses of 0.5 -50 nmol dose-dependently attenuated the second, but not the first, phase of the formalin-induced nociception, which was partially reversed by mevalonate (5 ...

Gabapentin Prevents Oxaliplatin-Induced Mechanical Hyperalgesia in Mice

“…Repeated treatment with simvastatin and rosuvastatin also pro duced an antihyperalgesic effect in mice and rats with nerve injuryinduced neuropathic pain (18). Recently, we also reported that intrathecal, but not intracerebroven tricular, administration of simvastatin exerted an antino ciceptive effect in formalininduced nociception (19). In contrast to these studies, our present results obtained using an oxaliplatininduced neuropathic pain model showed that neither simvastatin nor atorvastatin pro duced any antihyperalgesic or antiallodynic effects.…”

“…Systemic treatment with the lipidlowering drugs simvastatin and rosuvastatin attenuates thermal hyperal gesia and mechanical allodynia in nerveligated rats (18). We recently reported that intrathecal treatment with simvastatin attenuated the second, but not first, phase of the formalininduced nociceptive response, suggesting inhibition of the sensitization of spinal nociceptive trans mission (19). Therefore, these drugs are also expected to relieve the acute sensory paresthesias induced by oxaliplatin.…”

Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin

“…Moreover, Ohsawa et al (2012) suggest that simvastatininduced antinociception is mediated by attenuation of the sensitization of spinal nociceptive transmission. On the other hand, it is known that statins inhibit the synthesis of isoprenoids, including RhoA GTPase, which may contribute to the development of opioid tolerance and dependence (Goldstein and Brown, 1990).…”

Libidibia ferreaMature Seeds Promote Antinociceptive Effect by Peripheral and Central Pathway: Possible Involvement of Opioid and Cholinergic Receptors

“…The procedure used was similar to that described previously [10]. Twenty microliters of 2.5% formalin solution (95% formaldehyde) were injected intraplantarly (i.pl.)…”