Limits...
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.

Show MeSH

Related in: MedlinePlus

Iba1-positive cell density 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 Iba1-labeled microglia cells (red), plus DAPI-labeled cell nuclei (blue); scale bar: 50 μm. (b) Quantitative analysis of cellular density was 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 and **P < 0.01 versus vehicle + vehicle; ##P < 0.01 versus vehicle + morphine.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4385605&req=5

fig3: Iba1-positive cell density 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 Iba1-labeled microglia cells (red), plus DAPI-labeled cell nuclei (blue); scale bar: 50 μm. (b) Quantitative analysis of cellular density was 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 and **P < 0.01 versus vehicle + vehicle; ##P < 0.01 versus vehicle + morphine.

Mentions: Alkaloid treatment progressively increased the number of Iba1-positive cells in the dorsal horn (Figure 3). On day 6, microglia density was significantly higher in the group vehicle + morphine in comparison to vehicle + vehicle group. PEA fully prevented the morphine-induced microglia activation on day 6 and on day 11 the effect was still significant in comparison to vehicle + morphine (Figure 3). Similar results were obtained when microglia was analyzed by OX42 immunoreactivity (Supplemental information, Figure S1 available online at http://dx.doi.org/10.1155/2014/894732). The expression of GFAP in the dorsal horn is shown in Figure 4. The analysis of GFAP-positive cells reveals a morphine-induced increase in astrocyte cell density on day 6 as well as on day 11 (vehicle + morphine). PEA reduced astrocyte cell number at both time points (Figure 4; PEA + morphine).


Delay of morphine tolerance by palmitoylethanolamide.

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

Iba1-positive cell density 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 Iba1-labeled microglia cells (red), plus DAPI-labeled cell nuclei (blue); scale bar: 50 μm. (b) Quantitative analysis of cellular density was 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 and **P < 0.01 versus vehicle + vehicle; ##P < 0.01 versus vehicle + morphine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385605&req=5

fig3: Iba1-positive cell density 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 Iba1-labeled microglia cells (red), plus DAPI-labeled cell nuclei (blue); scale bar: 50 μm. (b) Quantitative analysis of cellular density was 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 and **P < 0.01 versus vehicle + vehicle; ##P < 0.01 versus vehicle + morphine.
Mentions: Alkaloid treatment progressively increased the number of Iba1-positive cells in the dorsal horn (Figure 3). On day 6, microglia density was significantly higher in the group vehicle + morphine in comparison to vehicle + vehicle group. PEA fully prevented the morphine-induced microglia activation on day 6 and on day 11 the effect was still significant in comparison to vehicle + morphine (Figure 3). Similar results were obtained when microglia was analyzed by OX42 immunoreactivity (Supplemental information, Figure S1 available online at http://dx.doi.org/10.1155/2014/894732). The expression of GFAP in the dorsal horn is shown in Figure 4. The analysis of GFAP-positive cells reveals a morphine-induced increase in astrocyte cell density on day 6 as well as on day 11 (vehicle + morphine). PEA reduced astrocyte cell number at both time points (Figure 4; PEA + morphine).

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