Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis

Abstract

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.

Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model

“…This observation may depend on the time of sampling or the small number of samples used. Although further studies on the present ex vivo model are merited, one should keep in mind that PEA‐um has been reported to decrease MC‐derived vasoactive mediators, both in vitro and in vivo . Moreover, the effect of systemic administration of PEA‐um on clinical signs sustained by dilation of cutaneous capillary vessels, including erythema, and the wheal and flare reaction, has been demonstrated in dogs …”

“…Although further studies on the present ex vivo model are merited, one should keep in mind that PEA-um has been reported to decrease MC-derived vasoactive mediators, both in vitro and in vivo. 23,28,40,43,51 Moreover, the effect of systemic administration of PEA-um on clinical signs sustained by dilation of cutaneous capillary vessels, including erythema, and the wheal and flare reaction, has been demonstrated in dogs. 7,9 In the present ex vivo model, exposing skin organ cultures to PEA-um for 96 h did not elicit any change in either the epidermal or dermal skin compartments, in terms of epidermal thickness or keratinocyte proliferation, the same pattern of keratinocyte differentiation markers, unchanged MC density and degranulation state, compared to vehicle-treated samples.…”

“…In the present study we used a canine skin organ culture model to show that PEA-um is able to counteract MC degranulation induced by administration of compound 40/ 80 and the subsequent vascular response. Although the effects of PEA in several inflammatory settings have been shown to depend, at least in part, upon the downmodulation of MC degranulation; [39][40][41][42][43] most available data rely on biochemical quantification of the released mediators, 24,43 focus on MC lines, 26,28 or primary MCs using in vitro conditions; 23 so they are outside the constitutive 3D environment of the skin. Here we present, to the best of the authors' knowledge for the first time, the use of a canine ex vivo model to study the degranulating state of MCs in situ, in response to a well-known secretagogue and document the effect of PEA-um.…”

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…This study found that the group's treatment led to decreased pain behaviors and decreased NGF in the mice [128]. Luvone et al [129] found NGF to play a role in both endometriosis- and ureteral calculosis-related pain. Specifically, ultramicronized palmitoylethanolamide (PEA-um) was noted to decrease pain-related behaviors in rat models of endometriosis and ureteral calculosis [129].…”

“…Luvone et al [129] found NGF to play a role in both endometriosis- and ureteral calculosis-related pain. Specifically, ultramicronized palmitoylethanolamide (PEA-um) was noted to decrease pain-related behaviors in rat models of endometriosis and ureteral calculosis [129]. The effect of PEA-um was linked to decreases in NGF (as well as other factors) [129].…”