Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia

Giuseppe D'Agostino, Giovanna La Rana, Roberto Russo, Oscar Sasso, Anna Iacono, Emanuela Esposito, Giuseppina Mattace Raso, Salvatore Cuzzocrea, Jesse LoVerme, Daniele Piomelli, Rosaria Meli, Antonio Calignano

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), a synthetic PPAR-alpha agonist. The obligatory role of PPAR-alpha in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-alpha. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-alpha in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.
Original languageEnglish
Pages (from-to)54-59
Number of pages6
JournalEuropean Journal of Pharmacology
Volume613
Issue number1-3
Early online date20 Apr 2009
DOIs
Publication statusPublished - 24 Jun 2009

Fingerprint

PPAR alpha
Hyperalgesia
Spinal Ganglia
NF-kappa B
Carrageenan
Central Nervous System
palmidrol
Non-Steroidal Anti-Inflammatory Agents
Nitric Oxide Synthase Type II
Sciatic Nerve
Cyclooxygenase 2
Lipid Metabolism
Fatty Acids
Pharmacology
Inflammation
Lipids
Pain
Injections

Keywords

  • analgesics
  • animals
  • butyrates
  • carrageenan
  • cell nucleus
  • central nervous system
  • cyclooxygenase 2
  • endocannabinoids
  • enzyme induction
  • ethanolamines
  • ganglia, spinal
  • hyperalgesia
  • male
  • mice
  • NF-kappa B
  • nitric oxide synthase type II
  • PPAR alpha
  • palmitic acids
  • phenylurea compounds
  • sciatic nerve
  • signal transduction

Cite this

Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia. / D'Agostino, Giuseppe; La Rana, Giovanna; Russo, Roberto; Sasso, Oscar; Iacono, Anna; Esposito, Emanuela; Mattace Raso, Giuseppina; Cuzzocrea, Salvatore; LoVerme, Jesse; Piomelli, Daniele; Meli, Rosaria; Calignano, Antonio.

In: European Journal of Pharmacology, Vol. 613, No. 1-3, 24.06.2009, p. 54-59.

Research output: Contribution to journalArticle

D'Agostino, G, La Rana, G, Russo, R, Sasso, O, Iacono, A, Esposito, E, Mattace Raso, G, Cuzzocrea, S, LoVerme, J, Piomelli, D, Meli, R & Calignano, A 2009, 'Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia', European Journal of Pharmacology, vol. 613, no. 1-3, pp. 54-59. https://doi.org/10.1016/j.ejphar.2009.04.022
D'Agostino, Giuseppe ; La Rana, Giovanna ; Russo, Roberto ; Sasso, Oscar ; Iacono, Anna ; Esposito, Emanuela ; Mattace Raso, Giuseppina ; Cuzzocrea, Salvatore ; LoVerme, Jesse ; Piomelli, Daniele ; Meli, Rosaria ; Calignano, Antonio. / Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia. In: European Journal of Pharmacology. 2009 ; Vol. 613, No. 1-3. pp. 54-59.
@article{fd7c153dde9f474e80eb33bc8410c965,
title = "Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia",
abstract = "Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), a synthetic PPAR-alpha agonist. The obligatory role of PPAR-alpha in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-alpha. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-alpha in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.",
keywords = "analgesics, animals, butyrates, carrageenan, cell nucleus, central nervous system, cyclooxygenase 2, endocannabinoids, enzyme induction, ethanolamines, ganglia, spinal, hyperalgesia, male, mice, NF-kappa B, nitric oxide synthase type II, PPAR alpha, palmitic acids, phenylurea compounds, sciatic nerve, signal transduction",
author = "Giuseppe D'Agostino and {La Rana}, Giovanna and Roberto Russo and Oscar Sasso and Anna Iacono and Emanuela Esposito and {Mattace Raso}, Giuseppina and Salvatore Cuzzocrea and Jesse LoVerme and Daniele Piomelli and Rosaria Meli and Antonio Calignano",
year = "2009",
month = "6",
day = "24",
doi = "10.1016/j.ejphar.2009.04.022",
language = "English",
volume = "613",
pages = "54--59",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "1-3",

}

TY - JOUR

T1 - Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-κB nuclear signalling in dorsal root ganglia

AU - D'Agostino, Giuseppe

AU - La Rana, Giovanna

AU - Russo, Roberto

AU - Sasso, Oscar

AU - Iacono, Anna

AU - Esposito, Emanuela

AU - Mattace Raso, Giuseppina

AU - Cuzzocrea, Salvatore

AU - LoVerme, Jesse

AU - Piomelli, Daniele

AU - Meli, Rosaria

AU - Calignano, Antonio

PY - 2009/6/24

Y1 - 2009/6/24

N2 - Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), a synthetic PPAR-alpha agonist. The obligatory role of PPAR-alpha in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-alpha. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-alpha in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.

AB - Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), a synthetic PPAR-alpha agonist. The obligatory role of PPAR-alpha in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-alpha. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-alpha in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.

KW - analgesics

KW - animals

KW - butyrates

KW - carrageenan

KW - cell nucleus

KW - central nervous system

KW - cyclooxygenase 2

KW - endocannabinoids

KW - enzyme induction

KW - ethanolamines

KW - ganglia, spinal

KW - hyperalgesia

KW - male

KW - mice

KW - NF-kappa B

KW - nitric oxide synthase type II

KW - PPAR alpha

KW - palmitic acids

KW - phenylurea compounds

KW - sciatic nerve

KW - signal transduction

U2 - 10.1016/j.ejphar.2009.04.022

DO - 10.1016/j.ejphar.2009.04.022

M3 - Article

C2 - 19386271

VL - 613

SP - 54

EP - 59

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1-3

ER -