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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: 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.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.

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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Related in: MedlinePlus

Analgesia measurement, paw pressure test. Animals were treated daily with 30 mg kg−1 PEA s.c. or with vehicle. The pain threshold was evaluated every day immediately before and 30 min after the injection i.p. of 10 mg kg−1 morphine. Each value represents the mean ± SEM of 12 rats per group, performed in 2 different experimental sets. **P < 0.01 versus pretest values.
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fig1: Analgesia measurement, paw pressure test. Animals were treated daily with 30 mg kg−1 PEA s.c. or with vehicle. The pain threshold was evaluated every day immediately before and 30 min after the injection i.p. of 10 mg kg−1 morphine. Each value represents the mean ± SEM of 12 rats per group, performed in 2 different experimental sets. **P < 0.01 versus pretest values.

Mentions: Ten mg kg−1 morphine administered i.p. (30 min after injection) increased the weight tolerated on the posterior paw up to 90.3 ± 2.7 g in comparison to the threshold before treatment (pretest) of 61.8 ± 1.2 g (Figure 1). A similar effect was maintained when morphine was newly injected in the following days till day 5. The same dose was unable to significantly increase pain threshold from day 6. In the group treated with 30 mg kg−1 PEA s.c. (daily) the antinociceptive effect of morphine reached 95.3 ± 1.7 g (Figure 1). The efficacy of morphine was significant up to day 10 (81.6 ± 2.9 g). PEA per se did not alter the response to the paw pressure as shown by the values of pretest (before morphine injection) of the group PEA + morphine. Figure 2 shows the results obtained with the plantar test. The withdrawal latency to a painful thermal stimulus was increased by morphine to 21.1 ± 2.7 s in comparison to the pretest value of 8.5 ± 0.5 s (vehicle + morphine group). In the presence of PEA treatment the significance of morphine-induced analgesia lasted till day 10 (14.8 ± 0.8 s).


Delay of morphine tolerance by palmitoylethanolamide.

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

Analgesia measurement, paw pressure test. Animals were treated daily with 30 mg kg−1 PEA s.c. or with vehicle. The pain threshold was evaluated every day immediately before and 30 min after the injection i.p. of 10 mg kg−1 morphine. Each value represents the mean ± SEM of 12 rats per group, performed in 2 different experimental sets. **P < 0.01 versus pretest values.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Analgesia measurement, paw pressure test. Animals were treated daily with 30 mg kg−1 PEA s.c. or with vehicle. The pain threshold was evaluated every day immediately before and 30 min after the injection i.p. of 10 mg kg−1 morphine. Each value represents the mean ± SEM of 12 rats per group, performed in 2 different experimental sets. **P < 0.01 versus pretest values.
Mentions: Ten mg kg−1 morphine administered i.p. (30 min after injection) increased the weight tolerated on the posterior paw up to 90.3 ± 2.7 g in comparison to the threshold before treatment (pretest) of 61.8 ± 1.2 g (Figure 1). A similar effect was maintained when morphine was newly injected in the following days till day 5. The same dose was unable to significantly increase pain threshold from day 6. In the group treated with 30 mg kg−1 PEA s.c. (daily) the antinociceptive effect of morphine reached 95.3 ± 1.7 g (Figure 1). The efficacy of morphine was significant up to day 10 (81.6 ± 2.9 g). PEA per se did not alter the response to the paw pressure as shown by the values of pretest (before morphine injection) of the group PEA + morphine. Figure 2 shows the results obtained with the plantar test. The withdrawal latency to a painful thermal stimulus was increased by morphine to 21.1 ± 2.7 s in comparison to the pretest value of 8.5 ± 0.5 s (vehicle + morphine group). In the presence of PEA treatment the significance of morphine-induced analgesia lasted till day 10 (14.8 ± 0.8 s).

Bottom Line: 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.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.

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