The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats.
BACKGROUND
Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats.


RESULTS
The effect of N-arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA-5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively.


CONCLUSIONS
These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain.
Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy.
Vito
V
de Novellis
Daniela
D
Vita
Luisa
L
Gatta
Livio
L
Luongo
Giulia
G
Bellini
Maria
M
De Chiaro
Ida
I
Marabese
Dario
D
Siniscalco
Serena
S
Boccella
Fabiana
F
Piscitelli
Vincenzo
V
Di Marzo
Enza
E
Palazzo
Francesco
F
Rossi
Sabatino
S
Maione
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology; D004558:Electric Stimulation; D004566:Electrodes; D055724:Electrophysiological Phenomena / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D020422:Mononeuropathies / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009619:Nociceptors / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C494484:TRPV1 receptor; C114007:arachidonoylserotonin; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4259-64
11259662
J Physiol. 2009 Jun 1;587(Pt 11):2521-35
19406878
Nature. 2002 Aug 1;418(6897):530-4
12152079
Brain Res. 1991 Nov 8;564(1):97-101
1777825
Curr Pharm Des. 2008;14(1):42-54
18220817
Eur J Neurosci. 2004 Jul;20(2):514-24
15233760
Neuron. 2008 Mar 13;57(5):746-59
18341994
Nature. 2003 Aug 21;424(6951):938-42
12931188
Annu Rev Neurosci. 2004;27:1-28
15217324
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3655-60
10725386
Curr Opin Pharmacol. 2001 Feb;1(1):66-72
11712538
Nature. 2003 Jul 17;424(6946):316-20
12867983
Science. 1997 Aug 15;277(5328):968-71
9252330
J Neurophysiol. 2002 Dec;88(6):3487-97
12466463
Neuroscience. 2006;139(3):1039-48
16527423
Neurosci Lett. 2006 Jan 30;393(2-3):255-9
16253423
Pain Res Manag. 2007 Winter;12(4):287-90
18080048
Clin J Pain. 1998 Jun;14(2):97-106
9647450
J Neurosci. 2004 Apr 7;24(14):3663-71
15071115
Pain. 2007 Nov;132(1-2):108-23
17449176
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):18004-9
19815518
Brain Res Rev. 2009 Apr;60(1):226-42
19162070
Pain. 2007 Jan;127(1-2):161-72
17055162
Neurosci Lett. 2006 Oct 23;407(2):176-81
16973269
Anal Biochem. 1976 May 7;72:248-54
942051
J Neurosci. 2008 Apr 9;28(15):3861-76
18400885
J Physiol. 2003 Apr 1;548(Pt 1):131-8
12576493
Nat Neurosci. 2007 Apr;10(4):462-8
17334362
J Neurosci. 2008 Nov 26;28(48):13003-7
19036993
Pain. 2008 Jul 15;137(2):413-421
18022320
J Cell Biochem. 1999 Apr 1;73(1):97-105
10088728
Science. 2004 Feb 20;303(5661):1162-7
14976306
J Neurosci. 2006 Nov 22;26(47):12165-73
17122041
Brain Res. 1996 May 13;720(1-2):211-9
8782914
Br J Pharmacol. 1999 Sep;128(2):428-34
10510454
J Neurosci. 2006 Jun 14;26(24):6458-68
16775133
Neurosci Lett. 1989 Mar 13;98(1):91-5
2540460
Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1622-9
17347454
Nat Rev Neurosci. 2004 Oct;5(10):793-807
15378039
Mol Pain. 2006 Nov 08;2:34
17092351
J Neurosci. 2007 Dec 12;27(50):13739-49
18077685
J Neurophysiol. 2009 May;101(5):2411-22
19297510
Pain. 2000 Aug;87(2):149-158
10924808
Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S79-83
18325659
J Neurosci. 2003 Apr 15;23(8):3136-44
12716921
J Neurosci. 2010 Apr 14;30(15):5451-64
20392966
Curr Opin Neurobiol. 2004 Apr;14(2):148-55
15082318
J Neurophysiol. 1998 Dec;80(6):3312-20
9862924
Pain. 2002 Mar;96(1-2):153-62
11932071
Neuroscience. 2006 Sep 29;142(1):1-20
16887277
Mol Pain. 2006 Oct 19;2:33
17052333
J Neurosci. 2004 Nov 17;24(46):10410-5
15548656
J Neurophysiol. 2006 Aug;96(2):579-90
16611846
J Neurosci. 2009 Nov 11;29(45):14299-308
19906977
J Neurosci. 2002 Apr 15;22(8):3206-14
11943821
J Neurosci. 2008 Jul 16;28(29):7445-53
18632948
Nature. 2005 Dec 15;438(7070):1017-21
16355225
Brain Res. 2007 Sep 12;1169:34-43
17698048
Science. 1992 Dec 18;258(5090):1946-9
1470919
J Neurosci. 2003 Nov 5;23(31):9987-95
14602812
Am J Clin Pathol. 2002 Jul;118(1):110-21
12109845
Neuroscientist. 2004 Jun;10(3):221-34
15155061
Trends Neurosci. 2008 Apr;31(4):199-207
18329111
J Pharmacol Exp Ther. 2006 Mar;316(3):969-82
16284279
Neuropharmacology. 2008 Dec;55(7):1105-13
18616956
Biochim Biophys Acta. 2007 Aug;1772(8):937-46
17616360
Science. 2006 Jun 16;312(5780):1659-62
16778058
Cereb Cortex. 1998 Jul-Aug;8(5):437-50
9722087
J Neurosci. 2005 Jun 29;25(26):6066-75
15987936
Neuron. 2004 Sep 16;43(6):897-905
15363399
J Neurophysiol. 2007 Jun;97(6):3893-904
17392412
Brain Res. 2004 Jan 9;995(2):176-83
14672807
Nature. 2008 Jul 31;454(7204):600-6
18615015
Eur J Pharmacol. 2009 Jan 28;603(1-3):42-9
19100257
Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2423-8
19171885
Eur J Pain. 2000;4(1):83-96
10833558
J Neurosci. 2007 Feb 21;27(8):2045-57
17314300
J Comp Neurol. 1990 Aug 1;298(1):40-9
1698828
Neuron. 2007 Mar 1;53(5):735-46
17329212
Br J Pharmacol. 2007 Mar;150(6):766-81
17279090
Biochem J. 1997 Mar 1;322 ( Pt 2):671-7
9065792
Pain. 2004 Mar;108(1-2):129-36
15109516
Biochem Biophys Res Commun. 1998 Jul 30;248(3):515-22
9703957
Eur J Pain. 1999 Jun;3(2):103-113
10700340
J Neurochem. 1985 Apr;44(4):1266-73
2579207
Neuroscience. 2006;139(4):1405-15
16603318
Science. 2003 Feb 21;299(5610):1237-40
12595694
Nature. 1999 Nov 18;402(6759):294-6
10580500
Annu Rev Biophys Biomol Struct. 2005;34:71-90
15869384
Neuroscience. 2008 Jun 23;154(2):621-30
18456414
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):8077-82
11416168
Neuron. 2002 Jul 18;35(2):383-93
12160755
Mol Pain. 2008 Jun 23;4:24
18573207
J Neurosci Res. 2006 Oct;84(5):927-33
16862566