The amplitude of the depolarization-evoked Ca2+ transient is larger in dorsal root ganglion (DRG) neurons from
tumor-bearing mice compared with that of neurons from naive mice, and the change is mimicked by coculturing DRG neurons with the
fibrosarcoma cells used to generate the
tumors (Khasabova et al., 2007). The effect of
palmitoylethanolamide (PEA), a
ligand for the
peroxisome proliferator-activated receptor α (PPARα), was determined on the evoked-Ca2+ 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 PPARα agonist (
GW7647), or
ARN077, an inhibitor of the
enzyme that hydrolyzes PEA, acutely decreased the amplitude of the evoked Ca2+ transient in small DRG neurons cocultured with
fibrosarcoma cells. The PPARα antagonist
GW6471 blocked the effect of each. In contrast, the PPARα agonist was without effect in the control condition, but the antagonist increased the amplitude of the Ca2+ transient, suggesting that PPARα receptors are saturated by endogenous
ligand under basal conditions. Effects of drugs on mechanical sensitivity in vivo paralleled their effects on DRG neurons in vitro. 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 PPARα-dependent mechanism. Moreover, agents that increase the activity of PPARα may provide a therapeutic strategy to reduce
tumor-evoked
pain.