Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system

Palazzo, Enza; De Novellis, Vito; Petrosino, Stefania; Marabese, Ida; Vita, Daniela; Giordano, Catia; Di Marzo, Vincenzo; Mangoni, Giuseppe Salvatore; Rossi, Francesco; Maione, Sabatino

doi:10.1111/j.1460-9568.2006.05086.x

Cited by 86Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsIon Channels and Receptors

Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system

Palazzo, Enza, De Novellis, Vito, Petrosino, Stefania, Marabese, Ida, Vita, Daniela, Giordano, Catia, Di Marzo, Vincenzo, Mangoni, Giuseppe Salvatore +2 more·2006·European Journal of Neuroscience

DOI 10.1111/j.1460-9568.2006.05086.x

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Abstract

We used a model of neuropathic pain consisting of rats with chronic constriction injury (CCI) of the sciatic nerve, in order to investigate whether endocannabinoid levels are altered in the dorsal raphe (DR) and to assess the effect of repeated treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate, a synthetic cannabinoid agonist, or N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404), an inhibitor of endocannabinoid reuptake, on DR serotonergic neuronal activity and on behavioural hyperalgesia. CCI resulted in significantly elevated anandamide but not 2-arachidonoylglycerol levels in the DR. Furthermore, as well as thermal and mechanical hyperalgesia, CCI caused serotonergic hyperactivity (as shown by the increase of basal activity of serotonergic neurones, extracellular serotonin levels and expression of 5-HT1A receptor gene). Repeated treatment with either (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate or AM404 reverted the hyperalgesia and enhanced serotonergic activity induced by CCI in a way attenuated by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide, a selective cannabinoid subtype 1 (CB1) receptor antagonist. Despite the elevated levels of anandamide following CCI, N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide did not produce hyperalgesia or any other effect on serotonergic neuronal activity when administered alone. Furthermore, the effects of AM404 were not accompanied by an increase in endocannabinoid levels in the DR. In conclusion, following CCI of the sciatic nerve, the endocannabinoid and serotonergic systems are activated in the DR, where repeated stimulation of CB1 receptors with exogenous compounds restores DR serotonergic activity, as well as thermal and mechanical nociceptive thresholds, to pre-surgery levels. However, an elevated level of endogenous anandamide in the DR does not necessarily contribute to the CB1-mediated tonic control of analgesia and serotonergic neuronal activity.

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CCI increases levels of endogenous AEA, but not 2-AG, in the dorsal raphe.
“CCI also increases levels of endogenous AEA, but not 2-AG, in the dorsal raphe – an observation which may help explain the anti-hyperalgesic efficacy of an anandamide transport inhibitor in this model.57”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [57]
CCI increases serotonin levels in the dorsal raphe, and this effect is suppressed by both WIN55,212-2 and AM404 in a CB1-dependent manner.
“CCI increases serotonin (5-HT) levels in the dorsal raphe and this effect was suppressed by both WIN55,212-2 and AM404 in a CB1-dependent manner.57”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [57]

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Authors: Palazzo, E., De Novellis, V., Petrosino, S., Marabese, I., Vita, D., Giordano, C., Di Marzo, V., Mangoni, G. S., Rossi, F., & Maione, S.
Affiliations: University of Campania "Luigi Vanvitelli" (IT)
Istituto di Chimica Biomolecolare (IT)
Corresponding author: Maione, Sabatino
ORCID: Petrosino, Stefania
Rossi, Francesco
Maione, Sabatino
Venue: European Journal of Neuroscience
Publisher: Wiley
Published: 2006-10
Volume: 24
Issue: 7
Pages: 2011-2020
ISSN: 0953-816X (ISSN-L)
1460-9568
DOI: 10.1111/j.1460-9568.2006.05086.x
OpenAlex: W2056843389
Cited by: 86
References: 59
Citations by year: 2026: 2 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 2 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 3 · 2013: 10 · 2012: 4
FWCI: 5.64
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 12 d)
Locations: European Journal of Neuroscience (publishedVersion)
PubMed (publishedVersion)
Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
Funders: Sanofi
Ministero dell’Istruzione, dell’Università e della Ricerca
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords: neuropathic pain, endocannabinoid system, dorsal raphe nucleus, chronic constriction injury, sciatic nerve, anandamide, 2-arachidonoylglycerol, serotonergic neurons, 5-HT1A receptor, AM404, cannabinoid receptor agonists, CB1 receptor, hyperalgesia
MeSH terms: Rimonabant, Action Potentials, Analysis of Variance, Animals, Arachidonic Acids, Behavior, Animal, Disease Models, Animal, Drug Interactions, Hot Temperature, Hyperalgesia, Male, Morpholines, Naphthalenes, Neurons, Pain Measurement, Piperidines, Pyrazoles, Raphe Nuclei, Reaction Time, Serotonin, Touch, Rats, Wistar, Microdialysis, Sciatic Neuropathy, Benzoxazines, Rats, Cannabinoid Receptor Modulators, Endocannabinoids

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Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system

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