The analgesic effect of N-arachidonoyl-serotonin, a FAAH inhibitor and TRPV1 receptor antagonist, associated with changes in rostral ventromedial medulla and locus coeruleus cell activity in rats.
We evaluated the effects of intra-periaqueductal grey (PAG) N-arachidonoyl-serotonin (AA-5-HT), a compound with a "dual" ability to inhibit the fatty acid amide hydrolase (FAAH) and to antagonize transient receptor vanilloid type 1 (TRPV1) receptors, on endocannabinoid levels, rostral ventromedial medulla (RVM) ON and OFF cell activities, thermal nociception (tail flick in anaesthetized rats) and formalin-induced nocifensive responses in awake rats. AA-5-HT increased endocannabinoid levels in the PAG and induced analgesia. Paradoxically, it also depressed the RVM OFF cell, as well as the ON cell activities. The effect of AA-5-HT was mimicked by co-injecting the selective FAAH inhibitor URB597 and the selective TRPV1 antagonist I-RTX into the PAG, which also induced analgesia and inhibition of ON and OFF cell ongoing activities. The recruitment of "alternative" pathways, such as PAG-locus coeruleus (LC)-spinal cord might be responsible for AA-5-HT effect since we found evidence that (i) intra-PAG AA-5-HT increased LC neuron firing activities, and (ii) intrathecal phentolamine or ketanserin prevented the analgesic effect of AA-5-HT. Moreover, intra-PAG AA-5-HT prevented the changes in the ON and OFF cells firing activity induced by intra-paw formalin, and it inverted the formalin-induced increase in LC adrenergic cell activity. All AA-5-HT effects were antagonized by cannabinoid CB1 and TRPV1 receptor antagonists thus suggesting that co-localization of these receptors in the PAG can be an appropriate neural substrate for AA-5-HT-induced analgesia.
de Novellis
Vito
V
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy.
Palazzo
Enza
E
Rossi
Francesca
F
De Petrocellis
Luciano
L
Petrosino
Stefania
S
Guida
Francesca
F
Luongo
Livio
L
Migliozzi
Annalucia
A
Cristino
Luigia
L
Marabese
Ida
I
Starowicz
Katarzyna
K
Di Marzo
Vincenzo
V
Maione
Sabatino
S
D018674:Adrenergic Antagonists / Q000494:pharmacology; D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000700:Analgesics; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D004594:Electrophysiology; D063388:Endocannabinoids; D004983:Ethanolamines; D005110:Extracellular Space / Q000187:drug effects; D005557:Formaldehyde; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D009829:Oleic Acids / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010169:Palmitic Acids / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D000099252:Fatty Acid Amide Hydrolases
D018674:Adrenergic Antagonists; D000577:Amides; D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D005557:Formaldehyde; D009829:Oleic Acids; D010169:Palmitic Acids; D012701:Serotonin; D012702:Serotonin Antagonists; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C494484:TRPV1 receptor; C114007:arachidonoylserotonin; C488250:oleoylethanolamide; C005958:palmidrol