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Palmitoylethanolamide Reduces Granuloma-Induced Hyperalgesia by Modulation of Mast Cell Activation in Rats

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Palmitoylethanolamide Reduces Granuloma-Induced Hyperalgesia by Modulation of Mast Cell Activation in Rats

Daniele De Filippis et al. Mol Pain.

Abstract

The aim of this study was to obtain evidences of a possible analgesic role for palmitoylethanolamide (PEA) in chronic granulomatous inflammation sustained by mast cell (MC) activation in rats at 96 hours. PEA (200-400-800 μg/mL), locally administered at time 0, reduced in a concentration-dependent manner the expression and release of NGF in comparison with saline-treated controls. PEA prevented nerve formation and sprouting, as shown by histological analysis, reduced mechanical allodynia, evaluated by Von Frey filaments, and inhibited dorsal root ganglia activation. These results were supported by the evidence that MCs in granuloma were mainly degranulated and closely localized near nerve fibres and PEA significantly reduced MC degranulation and nerves fibre formation. These findings are the first evidence that PEA, by the modulation of MC activation, controls pain perception in an animal model of chronic inflammation, suggesting its potential use for the treatment of all those painful conditions in which MC activation is an initial key step.

Figures

Figure 1
Figure 1
Effect of PEA on λ-carrageenin-induced mast cell activation. "A" shows the effect of PEA on λ-carrageenin-induced mast cell (MC) activation. MC degranulation was evaluated by microscopy. Connective MCs stained with 0.05% (w/v) toluidine blue and counterstained with 0.1% (w/v) nuclear fast red (magnification 100×). A differentiation between non degranulated (deep blue) and degranulated (light blue) MC was evaluable (a; b; c). In d) is shown the percentage of MC degranulation (ratio between degranulated and non degranulated MC). Results are expressed as mean ± SEM of 3 experiments. ***p < 0.001, °°p < 0.01. "B" shows high magnification of a representative histological analysis of granulomatous tissues stained with toluidine blue in which the presence of degranulated MCs is clearly visible close to blood vessels and nerves.
Figure 2
Figure 2
Effect of PEA on λ-carrageenin-induced NGF expression and release in granulomatous tissue r 96 h after PEA administration. (A) Representative Western blot analysis and relative densitometric analysis of NGF. Tubulin expression is shown as a control. (B) ELISA assay of NGF release in granulomatous tissue. Data are representative of 3 separate experiments. Results are expressed as mean ± SEM of 3 experiments.; *p < 0.05, **p < 0.01, ***p < 0.001 vs. saline.; °p < 0.05, °°p < 0.01, °°°p < 0.001 vs. λ-carrageenin alone.
Figure 3
Figure 3
Effect of PEA on λ-carrageenin-induced neurogenesis. (A) Nerves formation was evaluated in representative histological analysis of granulomatous tissue stained with hematoxyl and eosin. Fields are representative of 3 separate experiments. Original magnification, 100×. (B) Representative Western blot analysis and relative densitometric analysis of PGP 9.5 protein expression, as a marker of neuronal cells. Results are expressed as mean ± SEM of 3 experiments. *p < 0.05, **p < 0.01, ***p < 0.001 vs. saline; °p < 0.05, °°p < 0.01, °°°p < 0.001 vs. λ-carrageenin alone.
Figure 4
Figure 4
Effect of PEA on λ-carrageenin-induced hyperalgesia. Mechanical allodynia was evaluated by von Frey filament as (A) a target force both centrally and externally to granulomatous tissue and as (B) the frequency of withdrawals induced by 10 consecutive applications of the same von Frey filament. Results are expressed as mean ± SEM of 3 experiments. *p < 0.05, **p < 0.01, ***p < 0.001 vs. saline; °p < 0.05, °°p < 0.01, °°°p < 0.001 vs λ-carrageenin alone.
Figure 5
Figure 5
Effect of PEA on DRG biomolecular and morphological changes induced by granuloma. The effect of granulomatous inflammation on the biomolecular and morphological changes in the DRGs was associated with increased expression of TNF-α (A), NGF (B) and COX-2 (C). The levels of all proteins studied were significantly reduced by PEA treatment as revealed by Western blot analysis (A, B and C upper panels). Our results show that TNF-α and NGF were expressed by neurons as revealed by double labeling with TRPV1 receptor expressed in the DRG (A and B bottom panel) while COX-2 was highly expressed by satellite glial cells identified by glutamine synthetase staining (C bottom panel). Results are expressed as mean ± SEM of 3 experiments. ***p < 0.001 vs saline; °°°p < 0.001 vs λ-carrageenin alone.

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