Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha.
Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-alpha (peroxisome proliferator-activated receptor-alpha) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-alpha 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-alpha-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(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-alpha agonists may inhibit nocifensive responses by acting on peripheral PPAR-alpha. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-alpha was expressed in dorsal root ganglia neurons of wild-type but not PPAR-alpha-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-alpha expression and were observed following either acute or subchronic PPAR-alpha 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-alpha agonists may represent a novel class of analgesics.
LoVerme
Jesse
J
Department of Pharmacology, Center for Drug Discovery, University of California, Irvine, CA 92697-4625, USA.
Russo
Roberto
R
La Rana
Giovanna
G
Fu
Jin
J
Farthing
Jesse
J
Mattace-Raso
Giuseppina
G
Meli
Rosaria
R
Hohmann
Andrea
A
Calignano
Antonio
A
Piomelli
Daniele
D
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004361:Drug Tolerance; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D005557:Formaldehyde; D006930:Hyperalgesia / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D012585:Sciatica / Q000188:drug therapy
D000700:Analgesics; D018076:DNA, Complementary; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D024681:Potassium Channels, Calcium-Activated; D005557:Formaldehyde; D012313:RNA; C006012:fenofibric acid; D011345:Fenofibrate