Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-α

Abstract

Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-␣ (peroxisome proliferator-activated receptor-␣) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-␣ agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and palmitoylethanolamide (PEA) reduced nocifensive behaviors elicited in mice by intraplantar (i.pl.) injection of formalin or i.p. injection of magnesium sulfate. These effects were absent in PPAR-␣-null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcriptionindependent mechanism. Consistent with this hypothesis, blockade of calcium-operated IK ca (K Ca 3.1) and BK ca (K Ca 1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR-␣ agonists may inhibit nocifensive responses by acting on peripheral PPAR-␣. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-␣ was expressed in dorsal root ganglia neurons of wildtype but not PPAR-␣-null mice; and (ii) GW7647 and PEA prevented formalin-induced firing of spinal cord nociceptive neurons in rats. In addition to modulating nociception, GW7647 and PEA reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain; these effects were also contingent on PPAR-␣ expression and were observed following either acute or subchronic PPAR-␣ agonist administration. Finally, acute administration of GW7647 and PEA reduced hyperalgesic responses in the complete Freund's adjuvant and carrageenan models of inflammatory pain. Our results suggest that PPAR-␣ agonists may represent a novel class of analgesics.Current therapies do not control safely and effectively severe pain states-a broad spectrum of debilitating conditions that comprises acute, persistent inflammatory, and neuropathic pain. Even widely used drugs, such as opiates (e.g., morphine) or anticonvulsants (e.g., gabapentin), are only active in a fraction of the patient population and produce multiple, often serious, side effects. Thus, despite continuing progress in analgesic drug discovery, the need for therapeutic agents capable of blocking abnormal pain sensation without impairing normal abilities remains largely unmet.PPAR-␣ is a nuclear receptor that serves important functions in lipid nutrient utilization and inflammation (Taylor et al., 2002;Kostadinova et al., 2005). Like other members of the nuclear receptor superfamily, PPAR-␣ is activated

A neuroscientist's guide to lipidomics

“…Interestingly, some lipid messengers do not require G-protein-coupled receptors to exert their function. For example, neurosteroids interact with membrane GABA-gated receptor channels to enhance neuronal inhibition 75 , whereas oleoylethanolamide and its analogue palmitoylethanolamide engage peroxisome proliferator-activated receptors-α in the cell cytosol and nucleus to regulate feeding 76 and pain 77,78 (fIG. 5).…”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…The fact that oral administration of um-PEA not only results in increased plasma levels of PEA, but also of other NAEs is interesting in terms of potential synergistic effects, as the NAEs do not all share the same molecular targets. Indeed, most of the effects of PEA on inflammation and pain are mediated by PPAR-α [5,11,13,61], whereas AEA mainly acts by activating cannabinoid receptors 1 and 2 [62,63], and vanilloid (transient receptor potential vanilloid 1) receptors [64][65][66], and OEA by activating G proteincoupled receptor 119 and PPAR-α [67,68]. Thus, the effects observed here upon um-PEA administration can be due to PEA activating its molecular targets, and also to PEA favoring the actions of other NAEs (e.g., AEA and OEA).…”

“…Since the 1990s, interest in the therapeutic potential of PEA has increased owing to the discovery of the effects of PEA in many preclinical paradigms for pain and chronic inflammation [2]. PEA has antinociceptive properties in several animal models [3][4][5], prevents neurotoxicity and neurodegeneration [6][7][8], and inhibits peripheral inflammation and mast cell degranulation [9,10]. These effects of PEA are not only observed when used as a drug (i.e., after direct administration) [11,12], but also when its endogenous levels are increased by blocking its catabolism [13].…”

A thickening network of lipids

“…In neurons and innate immune cells, these endogenous lipid amides are formed by cleavage of the phospholipid precursor, N-acylphosphatidylethanolamine, a process that is carried out by a specialized phospholipase D enzyme. One of the best-known members of this family, palmitoylethanolamide (PEA), produces profound analgesic and anti-inflammatory effects in animals by recruiting a nuclear receptor called peroxisome proliferator-activated receptor-a (PPAR-a) [4] (see Fig. 1).…”

“…Binding of an agonist ligand to PPAR-a promotes the translocation of this protein from the cytosol to the nucleus, and initiates a series of molecular events that culminate in the transcriptional repression of genes encoding for key proinflammatory proteins, such as tumor-necrosis factor-a, inducible nitric oxide synthase and cyclooxygenase-2 [11]. In addition to modulating gene expression, PPAR-a can suppress nociceptive fiber activity and behavioral pain responses through a rapid nongenomic mechanism, which might involve the opening of membrane potassium channels [4]. While the mechanism underlying PPAR-a-dependent antinociception is still unclear, its functional relevance is underscored by the marked analgesic properties demonstrated by PEA and other PPAR-a agonists in a variety of animal pain models [4].…”