Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

Abstract

Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain.

Serum levels of adiponectin, CCL3/MIP-1α, and CCL5/RANTES discriminate migraine from tension-type headache patients

“…CCL-3/MIP-1α is a pro-inflammatory chemokine that participates in acute and chronic inflammatory responses by recruiting T-cells, monocytes, dendritic, and NK cells, playing an important role in the pathogenesis of many inflammatory conditions 22 . CCL-3/MIP-1α also acts as a mediator of chronic pain 23 .…”

“…This molecule is also involved in sensory regulation and neuropathic pain 23 . CCL5/RANTES has been previously shown to be higher during migraine attacks 25 , but in the present study this molecule was higher in migraine regardless of presence of pain.…”

Alterations in the Expression of Transcription Factors PPARγ and NFκB in the Brain of Models of Chronic Pain

“…Interestingly, PPARγ agonists have been involved in the regulation of this adipose-specific plasma protein that possesses antiatherogenic properties [38]. Performing further analysis including other inflammatory mediators such as chemokines in the brain of SNT and ART models would be necessary to address this point [39].…”

“…Both in vitro and in vivo studies have demonstrated that neuronal PPARγ prevents COX-2 increase, which in turn may reduce prostaglandin synthesis [40]. Hence, the reduction of PPARγ in pain models might contribute towards the loss of control of COX-2 upregulation, ultimately causing pain.…”

Peroxisome Proliferator-Activated Receptor α in Lipid Metabolism and Atherosclerosis

“…Another group of endogenous ligands consists of lipid metabolites from saturated or unsaturated fatty acids. Examples of synthetic ligands that bind to PPARα are the fibrate class of hypolipidemic drugs (gemfibrozil, bezafibrate, and fenofibrate), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14643), some phthalate monoesters (monoethylhexyl phthalate), and herbicides (lactofen) [16,17].…”