Effects of intra-ventrolateral periaqueductal grey palmitoylethanolamide on thermoceptive threshold and rostral ventromedial medulla cell activity

Vito de Novellis, Livio Luongo, Francesca Guida, Luigia Cristino, Enza Palazzo, Roberto Russo, Ida Marabese, Giuseppe D'Agostino, Antonio Calignano, Francesca Rossi, Vincenzo Di Marzo, Sabatino Maione

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51 Citations (Scopus)


Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor-α (PPAR-α) ligand, exerts antinociceptive and anti-inflammatory effects. PEA (3 and 6 nmol) was microinjected in the ventrolateral periaqueductal grey (VL PAG) of male rats and effects on nociceptive responses and ongoing and tail flick-related activities of rostral ventromedial medulla (RVM) ON and OFF cells were recorded. Intra-PAG microinjection of PEA reduced the ongoing activity of ON and OFF cells and produced an increase in the latency of the nociceptive reaction. These effects were prevented by a selective PPAR-α antagonist, GW6471 and by a large-conductance Ca(2+)-activated K(+) channel inhibitor, charybdotoxin. Cannabinoid 1 (CB(1)) receptor blockade by AM251 increased the PEA-induced effect both on the ongoing activity of the ON cell and on the latency to tail flick without affecting the effect of PEA on the OFF cell. Conversely, a transient receptor potential vanilloid type 1 (TRPV(1)) blocker, I-RTX, had no effect on the ON cell activity and tail flick latency, whereas it blocked the PEA-induced decrease in ongoing activity of the OFF cell. PEA decreased the burst and increased the latency of tail flick-evoked onset of ON cell activity in a manner antagonised by GW6471 and charybdotoxin. AM251 and I-RTX, instead, enhanced these latter effects. In conclusion, intra-VL PAG PEA induces antinociceptive effects associated with a decrease in RVM ON and OFF cell activities. PPAR-α receptors mediate, and CB(1) and TRPV(1) receptors antagonise, PEA-induced effects within the PAG-RVM circuitry.
Original languageEnglish
Pages (from-to)41-50
Number of pages10
JournalEuropean Journal of Pharmacology
Issue number1-3
Early online date3 Dec 2011
Publication statusPublished - 15 Feb 2012

Bibliographical note

Copyright © 2011 Elsevier B.V. All rights reserved.


  • analgesics
  • animals
  • behavior, animal
  • endocannabinoids
  • ethanolamines
  • gene expression regulation
  • male
  • myelencephalon
  • neurons
  • nociception
  • PPAR alpha
  • palmitic acids
  • periaqueductal gray
  • potassium channels, calcium-activated
  • rats
  • rats, wistar
  • receptor, cannabinoid, CB1
  • TRPV cation channels
  • temperature


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