A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
01 05 2022
01 05 2022
Historique:
received:
10
02
2021
accepted:
15
09
2021
pubmed:
11
1
2022
medline:
20
4
2022
entrez:
10
1
2022
Statut:
ppublish
Résumé
CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB2EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB2EGFP but not CB2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB2EGFP, but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB2EGFP mice. EGFP fluorescence was coexpressed with CB2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.
Identifiants
pubmed: 35001054
doi: 10.1097/j.pain.0000000000002502
pii: 00006396-202205000-00007
pmc: PMC8942871
mid: NIHMS1742268
doi:
Substances chimiques
Antineoplastic Agents
0
CB2 receptor agonist LY2828360
0
Cannabinoids
0
Cytokines
0
Purines
0
Pyrans
0
Receptor, Cannabinoid, CB1
0
Receptor, Cannabinoid, CB2
0
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
834-851Subventions
Organisme : NIDA NIH HHS
ID : R01 DA041229
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA047858
Pays : United States
Organisme : NIDA NIH HHS
ID : R21 DA042584
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200417
Pays : United States
Organisme : NIDA NIH HHS
ID : T32 DA024628
Pays : United States
Organisme : NIDA NIH HHS
ID : P01 DA009158
Pays : United States
Organisme : NCI NIH HHS
ID : R43 CA241513
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.
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