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Delay of morphine tolerance by palmitoylethanolamide.

Di Cesare Mannelli L, Corti F, Micheli L, Zanardelli M, Ghelardini C - Biomed Res Int (2015)

Bottom Line: In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect.N-palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation.PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.

ABSTRACT
In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg(-1) PEA was subcutaneously daily administered in morphine treated rats (10 mg kg(-1) intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested.

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Colocalization of TNF-α and GFAP in the dorsal horn of the spinal cord. 30 mg kg−1 PEA s.c. and 10 mg kg−1 morphine i.p. were administered daily and immunohistochemical analysis was performed on days 6 and 11; (a) representative images of merged TNF-α (red), GFAP (green), and DAPI (blue) labeling; scale bar: 50 μm. (b) Quantitative analysis of the overlap coefficient for TNF-α and GFAP expression performed evaluating 6 animals for each group. Each value represents the mean ± SEM of 6 rats per group, performed in 2 different experimental sets. *P < 0.05 versus vehicle + vehicle; #P < 0.05 versus vehicle + morphine.
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fig6: Colocalization of TNF-α and GFAP in the dorsal horn of the spinal cord. 30 mg kg−1 PEA s.c. and 10 mg kg−1 morphine i.p. were administered daily and immunohistochemical analysis was performed on days 6 and 11; (a) representative images of merged TNF-α (red), GFAP (green), and DAPI (blue) labeling; scale bar: 50 μm. (b) Quantitative analysis of the overlap coefficient for TNF-α and GFAP expression performed evaluating 6 animals for each group. Each value represents the mean ± SEM of 6 rats per group, performed in 2 different experimental sets. *P < 0.05 versus vehicle + vehicle; #P < 0.05 versus vehicle + morphine.

Mentions: In dorsal horn homogenate TNF-α levels were measured (Table 1). Vehicle + morphine treated rats showed a 112% and 168% increase of the cytokine on days 6 and 11, respectively. PEA did not alter this increment. As shown in Figures 5 and 6, TNF-α localization was studied by immunohistochemistry. In the spinal dorsal horn of vehicle + vehicle treated rats, TNF-α immunoreactivity was scarcely colocalized with the microglial marker OX42 and the overlap coefficient was not modified by treatments (Figure 5). The colocalization of TNF-α with GFAP was more evident even though morphine repeated treatment did not alter the value. On the contrary, after 6 days of treatment, PEA (PEA + morphine) significantly increased the overlap between TNF-α and GFAP (Figure 6). On day 11, after the development of tolerance also in the PEA group, the cytokine presence in astrocytes decreased to the level of vehicle + morphine group (Figure 6). For all the immunochemical analyses no differences were highlighted in the vehicle + vehicle group on days 6 and 11.


Delay of morphine tolerance by palmitoylethanolamide.

Di Cesare Mannelli L, Corti F, Micheli L, Zanardelli M, Ghelardini C - Biomed Res Int (2015)

Colocalization of TNF-α and GFAP in the dorsal horn of the spinal cord. 30 mg kg−1 PEA s.c. and 10 mg kg−1 morphine i.p. were administered daily and immunohistochemical analysis was performed on days 6 and 11; (a) representative images of merged TNF-α (red), GFAP (green), and DAPI (blue) labeling; scale bar: 50 μm. (b) Quantitative analysis of the overlap coefficient for TNF-α and GFAP expression performed evaluating 6 animals for each group. Each value represents the mean ± SEM of 6 rats per group, performed in 2 different experimental sets. *P < 0.05 versus vehicle + vehicle; #P < 0.05 versus vehicle + morphine.
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Related In: Results  -  Collection

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Show All Figures
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fig6: Colocalization of TNF-α and GFAP in the dorsal horn of the spinal cord. 30 mg kg−1 PEA s.c. and 10 mg kg−1 morphine i.p. were administered daily and immunohistochemical analysis was performed on days 6 and 11; (a) representative images of merged TNF-α (red), GFAP (green), and DAPI (blue) labeling; scale bar: 50 μm. (b) Quantitative analysis of the overlap coefficient for TNF-α and GFAP expression performed evaluating 6 animals for each group. Each value represents the mean ± SEM of 6 rats per group, performed in 2 different experimental sets. *P < 0.05 versus vehicle + vehicle; #P < 0.05 versus vehicle + morphine.
Mentions: In dorsal horn homogenate TNF-α levels were measured (Table 1). Vehicle + morphine treated rats showed a 112% and 168% increase of the cytokine on days 6 and 11, respectively. PEA did not alter this increment. As shown in Figures 5 and 6, TNF-α localization was studied by immunohistochemistry. In the spinal dorsal horn of vehicle + vehicle treated rats, TNF-α immunoreactivity was scarcely colocalized with the microglial marker OX42 and the overlap coefficient was not modified by treatments (Figure 5). The colocalization of TNF-α with GFAP was more evident even though morphine repeated treatment did not alter the value. On the contrary, after 6 days of treatment, PEA (PEA + morphine) significantly increased the overlap between TNF-α and GFAP (Figure 6). On day 11, after the development of tolerance also in the PEA group, the cytokine presence in astrocytes decreased to the level of vehicle + morphine group (Figure 6). For all the immunochemical analyses no differences were highlighted in the vehicle + vehicle group on days 6 and 11.

Bottom Line: In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect.N-palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation.PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.

ABSTRACT
In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg(-1) PEA was subcutaneously daily administered in morphine treated rats (10 mg kg(-1) intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested.

Show MeSH
Related in: MedlinePlus