The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain.
There is considerable evidence to support the role of anandamide (AEA), an endogenous ligand of cannabinoid receptors, in neuropathic pain modulation. AEA also produces effects mediated by other biological targets, of which the transient receptor potential vanilloid type 1 (TRPV1) has been the most investigated. Both, inhibition of AEA breakdown by fatty acid amide hydrolase (FAAH) and blockage of TRPV1 have been shown to produce anti-nociceptive effects. Recent research suggests the usefulness of dual-action compounds, which may afford greater anti-allodynic efficacy. Therefore, in the present study, we examined the effect of N-arachidonoyl-serotonin (AA-5-HT), a blocker of FAAH and TRPV1, in a rat model of neuropathic pain after intrathecal administration. We found that treatment with AA-5-HT increased the pain threshold to mechanical and thermal stimuli, with highest effect at the dose of 500nM, which was most strongly attenuated by AM-630, CB2 antagonist, administration. The single action blockers PF-3845 (1000nM, for FAAH) and I-RTX (1nM, for TRPV1) showed lower efficacy than AA-5-HT. Moreover AA-5-HT (500nM) elevated AEA and palmitoylethanolamide (PEA) levels. Among the possible targets of these mediators, only the mRNA levels of CB2, GPR18 and GPR55, which are believed to be novel cannabinoid receptors, were upregulated in the spinal cord and/or DRG of CCI rats. It was previously reported that AA-5-HT acts in CB1 and TRPV1-dependent manner after systemic administration, but here for the first time we show that AA-5-HT action at the spinal level involves CB2, with potential contributions from GRP18 and/or GPR55 receptors.
Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland; Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: n.malek@if-pan.krakow.pl.
Natalia
N
Malek
Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland; Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: mkos@if-pan.krakow.pl.
Magdalena
M
Kostrzewa
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: makuch@if-pan.krakow.pl.
Wioletta
W
Makuch
Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland; Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: pajak@if-pan.krakow.pl.
Agnieszka
A
Pajak
Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland; Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: meshugemk@gmail.com.
Mateusz
M
Kucharczyk
Endocannabinoid Research Group, Institute of Biomolecular Chemistry⿿C.N.R., Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli (NA), Italy. Electronic address: fpiscitelli@icb.cnr.it.
Fabiana
F
Piscitelli
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: przebar@if-pan.krakow.pl.
Barbara
B
Przewlocka
Endocannabinoid Research Group, Institute of Biomolecular Chemistry⿿C.N.R., Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli (NA), Italy. Electronic address: vincenzo.dimarzo@icb.cnr.it.
Vincenzo
V
Di Marzo
Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland; Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland. Electronic address: starow@if-pan.krakow.pl.
Katarzyna
K
Starowicz
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D059225:Nociception / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; C588261:GPR18 protein, rat; C568825:GPR55 protein, rat; C493922:Trpv1 protein, rat; C114007:arachidonoylserotonin; C094503:glyceryl 2-arachidonate; C078814:anandamide
Cannabinoid receptors; Endocannabinoids; FAAH; N-acylethanolamines; Neuropathic pain; TRPV1