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Research ArticleNEUROPHARMACOLOGY

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

Jesse LoVerme, Roberto Russo, Giovanna La Rana, Jin Fu, Jesse Farthing, Giuseppina Mattace-Raso, Rosaria Meli, Andrea Hohmann, Antonio Calignano and Daniele Piomelli
Journal of Pharmacology and Experimental Therapeutics December 2006, 319 (3) 1051-1061; DOI: https://doi.org/10.1124/jpet.106.111385
Jesse LoVerme
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Roberto Russo
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Giovanna La Rana
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Jin Fu
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Jesse Farthing
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Giuseppina Mattace-Raso
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Rosaria Meli
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Andrea Hohmann
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Antonio Calignano
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Daniele Piomelli
Department of Pharmacology and the Center for Drug Discovery, University of California, Irvine, California (J.L., J.F. D.P.); Department of Experimental Pharmacology, University of Naples, Naples, Italy (R.R., G.L., G.M.R., R.M., A.C.); and Department of Psychology, University of Georgia, Athens, Georgia (J.F., A.H.)
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Abstract

Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-α (peroxisome proliferator-activated receptor-α) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-α 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-α-null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcription-independent mechanism. Consistent with this hypothesis, blockade of calcium-operated IKca (KCa3.1) and BKca (KCa1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR-α agonists may inhibit nocifensive responses by acting on peripheral PPAR-α. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-α was expressed in dorsal root ganglia neurons of wild-type but not PPAR-α-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-α expression and were observed following either acute or subchronic PPAR-α 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-α agonists may represent a novel class of analgesics.

  • Received July 24, 2006.
  • Accepted September 21, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleNEUROPHARMACOLOGY

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

Jesse LoVerme, Roberto Russo, Giovanna La Rana, Jin Fu, Jesse Farthing, Giuseppina Mattace-Raso, Rosaria Meli, Andrea Hohmann, Antonio Calignano and Daniele Piomelli
Journal of Pharmacology and Experimental Therapeutics December 1, 2006, 319 (3) 1051-1061; DOI: https://doi.org/10.1124/jpet.106.111385

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Research ArticleNEUROPHARMACOLOGY

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

Jesse LoVerme, Roberto Russo, Giovanna La Rana, Jin Fu, Jesse Farthing, Giuseppina Mattace-Raso, Rosaria Meli, Andrea Hohmann, Antonio Calignano and Daniele Piomelli
Journal of Pharmacology and Experimental Therapeutics December 1, 2006, 319 (3) 1051-1061; DOI: https://doi.org/10.1124/jpet.106.111385
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