Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain

Oscar Sasso, Roberto Russo, Sergio Vitiello, Giuseppina Mattace Raso, Giuseppe D'Agostino, Anna Iacono, Giovanna La Rana, Monique Vallée, Salvatore Cuzzocrea, Pier Vincenzo Piazza, Rosaria Meli, Antonio Calignano

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Abstract

We investigated the involvement of de novo neurosteroid synthesis in the mechanisms underlying the analgesic and antihyperalgesic effects of N-palmitoylethanolamine (PEA) in two models of acute and persistent pain, the formalin test and carrageenan-induced paw edema. The pivotal role of peroxisome proliferator-activated receptor (PPAR)-α in the antinocifensive effect of PEA was confirmed by the lack of this effect in PPAR-α-null mice. PEA antinociceptive activity was partially reduced when the animals were treated with aminoglutethimide or finasteride, implying that de novo neurosteroid synthesis is involved in the effect of PEA. Accordingly, in the spinal cord, the allopregnanolone (ALLO) levels were increased by PEA treatment both in formalin- and carrageenan-exposed mice, as revealed by gas chromatography-mass spectrometry. In agreement with those data, in both pain models, PEA administration in challenged mice specifically restored the expression of two proteins involved in neurosteroidogenensis, the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc) in the ipsilateral horns of spinal cord, without affecting their expression in the contralateral side. These results provide new information about the involvement of de novo neurosteroid synthesis in the modulation of pain behavior by PEA.
Original languageEnglish
Pages (from-to)33-41
Number of pages9
JournalPain
Volume153
Issue number1
DOIs
Publication statusPublished - Jan 2012

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Pregnanolone
Neurotransmitter Agents
Peroxisome Proliferator-Activated Receptors
Carrageenan
Pain
Spinal Cord
Aminoglutethimide
Finasteride
Acute Pain
Pain Measurement
Horns
Gas Chromatography-Mass Spectrometry
Cytochrome P-450 Enzyme System
Formaldehyde
Analgesics
Edema
palmidrol
Proteins
Therapeutics

Keywords

  • analgesics
  • animals
  • endocannabinoids
  • ethanolamines
  • hyperalgesia
  • male
  • mice
  • pain
  • pain measurement
  • palmitic acids
  • pregnanolone
  • spinal cord

Cite this

Sasso, O., Russo, R., Vitiello, S., Raso, G. M., D'Agostino, G., Iacono, A., ... Calignano, A. (2012). Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain. Pain, 153(1), 33-41. https://doi.org/10.1016/j.pain.2011.08.010

Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain. / Sasso, Oscar; Russo, Roberto; Vitiello, Sergio; Raso, Giuseppina Mattace; D'Agostino, Giuseppe; Iacono, Anna; Rana, Giovanna La; Vallée, Monique; Cuzzocrea, Salvatore; Piazza, Pier Vincenzo; Meli, Rosaria; Calignano, Antonio.

In: Pain, Vol. 153, No. 1, 01.2012, p. 33-41.

Research output: Contribution to journalArticle

Sasso, O, Russo, R, Vitiello, S, Raso, GM, D'Agostino, G, Iacono, A, Rana, GL, Vallée, M, Cuzzocrea, S, Piazza, PV, Meli, R & Calignano, A 2012, 'Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain', Pain, vol. 153, no. 1, pp. 33-41. https://doi.org/10.1016/j.pain.2011.08.010
Sasso, Oscar ; Russo, Roberto ; Vitiello, Sergio ; Raso, Giuseppina Mattace ; D'Agostino, Giuseppe ; Iacono, Anna ; Rana, Giovanna La ; Vallée, Monique ; Cuzzocrea, Salvatore ; Piazza, Pier Vincenzo ; Meli, Rosaria ; Calignano, Antonio. / Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain. In: Pain. 2012 ; Vol. 153, No. 1. pp. 33-41.
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abstract = "We investigated the involvement of de novo neurosteroid synthesis in the mechanisms underlying the analgesic and antihyperalgesic effects of N-palmitoylethanolamine (PEA) in two models of acute and persistent pain, the formalin test and carrageenan-induced paw edema. The pivotal role of peroxisome proliferator-activated receptor (PPAR)-α in the antinocifensive effect of PEA was confirmed by the lack of this effect in PPAR-α-null mice. PEA antinociceptive activity was partially reduced when the animals were treated with aminoglutethimide or finasteride, implying that de novo neurosteroid synthesis is involved in the effect of PEA. Accordingly, in the spinal cord, the allopregnanolone (ALLO) levels were increased by PEA treatment both in formalin- and carrageenan-exposed mice, as revealed by gas chromatography-mass spectrometry. In agreement with those data, in both pain models, PEA administration in challenged mice specifically restored the expression of two proteins involved in neurosteroidogenensis, the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc) in the ipsilateral horns of spinal cord, without affecting their expression in the contralateral side. These results provide new information about the involvement of de novo neurosteroid synthesis in the modulation of pain behavior by PEA.",
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AU - Vitiello, Sergio

AU - Raso, Giuseppina Mattace

AU - D'Agostino, Giuseppe

AU - Iacono, Anna

AU - Rana, Giovanna La

AU - Vallée, Monique

AU - Cuzzocrea, Salvatore

AU - Piazza, Pier Vincenzo

AU - Meli, Rosaria

AU - Calignano, Antonio

N1 - Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

PY - 2012/1

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N2 - We investigated the involvement of de novo neurosteroid synthesis in the mechanisms underlying the analgesic and antihyperalgesic effects of N-palmitoylethanolamine (PEA) in two models of acute and persistent pain, the formalin test and carrageenan-induced paw edema. The pivotal role of peroxisome proliferator-activated receptor (PPAR)-α in the antinocifensive effect of PEA was confirmed by the lack of this effect in PPAR-α-null mice. PEA antinociceptive activity was partially reduced when the animals were treated with aminoglutethimide or finasteride, implying that de novo neurosteroid synthesis is involved in the effect of PEA. Accordingly, in the spinal cord, the allopregnanolone (ALLO) levels were increased by PEA treatment both in formalin- and carrageenan-exposed mice, as revealed by gas chromatography-mass spectrometry. In agreement with those data, in both pain models, PEA administration in challenged mice specifically restored the expression of two proteins involved in neurosteroidogenensis, the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc) in the ipsilateral horns of spinal cord, without affecting their expression in the contralateral side. These results provide new information about the involvement of de novo neurosteroid synthesis in the modulation of pain behavior by PEA.

AB - We investigated the involvement of de novo neurosteroid synthesis in the mechanisms underlying the analgesic and antihyperalgesic effects of N-palmitoylethanolamine (PEA) in two models of acute and persistent pain, the formalin test and carrageenan-induced paw edema. The pivotal role of peroxisome proliferator-activated receptor (PPAR)-α in the antinocifensive effect of PEA was confirmed by the lack of this effect in PPAR-α-null mice. PEA antinociceptive activity was partially reduced when the animals were treated with aminoglutethimide or finasteride, implying that de novo neurosteroid synthesis is involved in the effect of PEA. Accordingly, in the spinal cord, the allopregnanolone (ALLO) levels were increased by PEA treatment both in formalin- and carrageenan-exposed mice, as revealed by gas chromatography-mass spectrometry. In agreement with those data, in both pain models, PEA administration in challenged mice specifically restored the expression of two proteins involved in neurosteroidogenensis, the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc) in the ipsilateral horns of spinal cord, without affecting their expression in the contralateral side. These results provide new information about the involvement of de novo neurosteroid synthesis in the modulation of pain behavior by PEA.

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KW - hyperalgesia

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KW - pregnanolone

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