title: Effects of intra-ventrolateral periaqueductal grey palmitoylethanolamide on thermoceptive threshold and rostral ventromedial medulla cell activity.
abstract: 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.
authors.affiliation: Endocannabinoid Research Group at the Department of Experimental Medicine, Division of Pharmacology "L. Donatelli", The Second University of Naples, 80138 Naples, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: de Novellis
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Ida
authors.initials: I
authors.lastname: Marabese
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
mesh_terms: D000577:Amides; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D063388:Endocannabinoids; D004983:Ethanolamines; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D054024:Myelencephalon / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059225:Nociception / Q000187:drug effects*; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000187:drug effects*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D013696:Temperature
chemical_list: D000577:Amides; D000700:Analgesics; D063388:Endocannabinoids; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; D024681:Potassium Channels, Calcium-Activated; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C005958:palmidrol