The effects of ultramicronized
palmitoylethanolamide were evaluated on
pain behaviours and markers of mast cell (MC) activity in a rat model of
endometriosis plus ureteral
calculosis (ENDO+STONE)-induced viscerovisceral
hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of
endometriosis were randomly assigned to receive active (ultramicronized
palmitoylethanolamide 10 mg·kg(-1)·d(-1), orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine
pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial
cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels,
chymase,
nerve growth factor (
NGF),
vascular endothelial growth factor (
VEGF), and
Flk-1 (VEGF receptor) in
cysts, and
NGF in dorsal root ganglia (DRG). Ultramicronized
palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine
pain, and smaller
cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P < 0.01), vessel number (P < 0.01),
chymase (P < 0.05),
NGF (P < 0.05),
VEGF (P < 0.01), and Flk-1 (P < 0.01) expression in
cysts and
NGF expression in DRG (P < 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with
cyst diameter, MC number and
chymase in
cysts, and
NGF in
cysts and DRG (0.02 < P < 0.0002). Ultramicronized
palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in
cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics.