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NEUROPHARMACOLOGY

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

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.)

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 transcription-independent mechanism. Consistent with this hypothesis, blockade of calcium-operated IK_ca (K_Ca3.1) and BK_ca (K_Ca1.1) 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 wild-type 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.

Address correspondence to: Dr. Daniele Piomelli, Department of Pharmacology, University of California, Irvine, 360 MSRII, Irvine, CA 92697-4625. E-mail: piomelli{at}uci.edu

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