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The effect of palmitoylethanolamide (PEA), a ligand for the peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1), was determined on the evoked-Ca<jats:sup>2+<\/jats:sup>transient in the coculture condition. The level of PEA was reduced in DRG cells from tumor-bearing mice as well as those cocultured with fibrosarcoma cells. Pretreatment with PEA, a synthetic PPAR\u03b1 agonist (GW7647), or ARN077, an inhibitor of the enzyme that hydrolyzes PEA, acutely decreased the amplitude of the evoked Ca<jats:sup>2+<\/jats:sup>transient in small DRG neurons cocultured with fibrosarcoma cells. The PPAR\u03b1 antagonist GW6471 blocked the effect of each. In contrast, the PPAR\u03b1 agonist was without effect in the control condition, but the antagonist increased the amplitude of the Ca<jats:sup>2+<\/jats:sup>transient, suggesting that PPAR\u03b1 receptors are saturated by endogenous ligand under basal conditions. Effects of drugs on mechanical sensitivity<jats:italic>in vivo<\/jats:italic>paralleled their effects on DRG neurons<jats:italic>in vitro<\/jats:italic>. Local injection of ARN077 decreased mechanical hyperalgesia in tumor-bearing mice, and the effect was blocked by GW6471. These data support the conclusion that the activity of DRG neurons is rapidly modulated by PEA through a PPAR\u03b1-dependent mechanism. 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