Atorvastatin inhibits inflammatory hypernociception

Abstract

Background and purpose: Atorvastatin is an inhibitor of the enzyme 3-hydroxyl-3-methylglutaryl coenzyme A reductase used to prevent coronary heart disease. We have studied the analgesic effect of atorvastatin in inflammatory models in which a sequential release of mediators (bradykinin, (BK), tumour necrosis factor-a (TNF-a), interleukin-1b (IL-1b) and the chemokine, KC/CXCL) links the stimulus with release of directly acting hypernociceptive mediators such as prostaglandin E 2 (PGE 2 ). Experimental approach: The effects of orally administered atorvastatin on inflammatory mechanical hypernociception in mouse paws were evaluated with an electronic pressure-meter. Cytokines and PGE 2 were measured by ELISA and RIA. Key results: Treatment with atorvastatin for 3 days dose-dependently reduced hypernociception induced by lipopolysaccharide (LPS) or that following antigen challenge in sensitized animals. Atorvastatin pre-treatment reduced hypernociception induced by bradykinin and cytokines (TNF-a, IL-1b and KC), and the release of IL-1b and PGE 2 in paw skin, induced by lipopolysaccharide. The antinociceptive effect of atorvastatin on LPS-induced hypernociception was prevented by mevalonate co-treatment without affecting serum cholesterol levels. Hypernociception induced by PGE 2 was inhibited by atorvastatin, suggesting intracellular antinociceptive mechanisms for atorvastatin. The antinociceptive effect of atorvastatin upon LPS-or PGE 2 -induced hypernociception was prevented by non-selective inhibitors of nitric oxide synthase (NOS) but not by selective inhibition of inducible NOS or in mice lacking this enzyme. Conclusions and implications: Antinociceptive effects of atorvastatin depend on inhibition of cytokines and prostanoid production and on stimulation of NO production by constitutive NOS. Our study suggests that statins may constitute a novel class of analgesic drugs.

Gabapentin Prevents Oxaliplatin-Induced Mechanical Hyperalgesia in Mice

“…Oxaliplatin modulates the activity of ionic channels, particularly voltagegated sodium channels (37,38). A previous study using hippocampal slices has shown that neurotransmission sensitization induced by theta burst stimulation (10 bursts of 4 pulses at 100 Hz with 200ms interburst intervals) induces phosphoryla tion of cofilin (39). Therefore, the increase of cofilin phosphorylation in the spinal cord induced by oxaliplatin might be caused by sensory nerve activation.…”

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

“…These carrageenan-activated inflammatory cascades are related not only to the innate immunity but also to the generation of reactive oxygen species (ROS) (34). Since inflammation is closely linked to the production of ROS, the molecular basis of the observed anti-inflammatory effects of statins may be related to their ability to block the production and/or activity of ROS (35). Therefore, the results of the present study indicate an anti-inflammatory effect of lovastatin on the paw edema and leukocyte migration in peritoneal exudate induced by carrageenan, inhibition of MPO release from in vitro human neutrophils, and an anti-nociceptive action in the formalin test.…”

Neuroprotective and Anti-Inflammatory Activities of Atorvastatin in a Rat Chronic Constriction Injury Model

“…Inflammatory hypemociceptive mediators, such as prostaglandins (PGs), considered to be directly acting on their specific metabotropic receptors present on the primary sensory neurons (33). PGE2, a pro-inflammatory prostanoid, exerts its effect by acting via PGE receptor subtypes, EPI to EP4 (34).…”