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 transcriptionindependent 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-_ was expressed in dorsal root ganglia neurons of wildtype 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.

Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha / J., Loverme; Russo, Roberto; LA RANA, Giovanna; J., Fu; J., Farthing; MATTACE RASO, Giuseppina; Meli, Rosaria; A., Hohmann; Calignano, Antonio; D., Piomelli. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - STAMPA. - 319:(2006), pp. 1051-1061. [10.1124/jpet.106.111385]

Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha.

RUSSO, ROBERTO;LA RANA, GIOVANNA;MATTACE RASO, GIUSEPPINA;MELI, ROSARIA;CALIGNANO, ANTONIO;
2006

Abstract

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 transcriptionindependent 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-_ was expressed in dorsal root ganglia neurons of wildtype 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.
2006
Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha / J., Loverme; Russo, Roberto; LA RANA, Giovanna; J., Fu; J., Farthing; MATTACE RASO, Giuseppina; Meli, Rosaria; A., Hohmann; Calignano, Antonio; D., Piomelli. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - STAMPA. - 319:(2006), pp. 1051-1061. [10.1124/jpet.106.111385]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/107303
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