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.