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Peripheral deficiency and antiallodynic effects of 2-arachidonoyl glycerol in a mouse model of paclitaxel-induced neuropathic pain.
Biomed Pharmacother. 2020 Sep; 129:110456.BP

Abstract

BACKGROUND

Modulation of the endocannabinoid system has been shown to alleviate neuropathic pain. The aim of this study was to evaluate if treatment with paclitaxel, a chemotherapeutic agent that induces neuropathic pain, affects endocannabinoid levels at a time when mice develop paclitaxel-induced mechanical allodynia. We also evaluated the peripheral antiallodynic activity of the endocannabinoid 2-arachidonoyl glycerol (2-AG) and an inhibitor of monoacylglycerol lipase (MAGL), an enzyme responsible for 2-AG hydrolysis.

METHODS

Female BALB/c mice were treated intraperitoneally with paclitaxel to induce mechanical allodynia. Levels of the endocannabinoids, N-arachidonoylethanolamine (anandamide, AEA), 2-AG, and the N-acylethanolamines (NAEs), N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), which are structurally-related to AEA, in the brain, spinal cord and paw skin were measured using LC-MS/MS. Protein expression of MAGL in the paw skin was measured using Wes™. The effects of subcutaneous (s.c.) injection of 2-AG and JZL184 (a MAGL inhibitor) into the right hind paw of mice with paclitaxel-induced mechanical allodynia were assessed using the dynamic plantar aesthesiometer. The effects of pretreatment, s.c., into the right hind paw, with cannabinoid type 1 (CB1) receptor antagonist AM251 and CB2 receptor antagonist AM630 on the antiallodynic effects of 2-AG were also evaluated.

RESULTS

The levels of 2-AG were reduced only in the paw skin of paclitaxel-treated mice, whilst the levels of AEA, PEA and OEA were not significantly altered. There was no change in the expression of MAGL in the paw skin. Administration of 2-AG and JZL184 produced antiallodynic effects against paclitaxel-induced mechanical allodynia in the injected right paw, but did not affect the uninjected left paw. The antiallodynic activity of 2-AG was antagonized by both AM251 and AM630.

CONCLUSION

These results indicate that during paclitaxel-induced mechanical allodynia there is a deficiency of 2-AG in the periphery, but not in the CNS. Increasing 2-AG in the paw by local administration of 2-AG or a MAGL inhibitor, alleviates mechanical allodynia in a CB1 and CB2 receptor-dependent manner.

Authors+Show Affiliations

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.Pharmacology and Therapeutics, School of Medicine, NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, University Road, Galway, Ireland.Pharmacology and Therapeutics, School of Medicine, NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, University Road, Galway, Ireland.Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait. Electronic address: masocha@hsc.edu.kw.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32603895

Citation

Thomas, Amal, et al. "Peripheral Deficiency and Antiallodynic Effects of 2-arachidonoyl Glycerol in a Mouse Model of Paclitaxel-induced Neuropathic Pain." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 129, 2020, p. 110456.
Thomas A, Okine BN, Finn DP, et al. Peripheral deficiency and antiallodynic effects of 2-arachidonoyl glycerol in a mouse model of paclitaxel-induced neuropathic pain. Biomed Pharmacother. 2020;129:110456.
Thomas, A., Okine, B. N., Finn, D. P., & Masocha, W. (2020). Peripheral deficiency and antiallodynic effects of 2-arachidonoyl glycerol in a mouse model of paclitaxel-induced neuropathic pain. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 129, 110456. https://doi.org/10.1016/j.biopha.2020.110456
Thomas A, et al. Peripheral Deficiency and Antiallodynic Effects of 2-arachidonoyl Glycerol in a Mouse Model of Paclitaxel-induced Neuropathic Pain. Biomed Pharmacother. 2020;129:110456. PubMed PMID: 32603895.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peripheral deficiency and antiallodynic effects of 2-arachidonoyl glycerol in a mouse model of paclitaxel-induced neuropathic pain. AU - Thomas,Amal, AU - Okine,Bright N, AU - Finn,David P, AU - Masocha,Willias, Y1 - 2020/06/27/ PY - 2020/04/21/received PY - 2020/06/16/revised PY - 2020/06/23/accepted PY - 2020/7/1/pubmed PY - 2021/3/2/medline PY - 2020/7/1/entrez KW - 2-Arachidonoyl glycerol KW - Allodynia KW - Cannabinoid receptors KW - Chemotherapy-induced neuropathic pain KW - Endocannabinoid KW - Monoacylglycerol lipase SP - 110456 EP - 110456 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed Pharmacother VL - 129 N2 - BACKGROUND: Modulation of the endocannabinoid system has been shown to alleviate neuropathic pain. The aim of this study was to evaluate if treatment with paclitaxel, a chemotherapeutic agent that induces neuropathic pain, affects endocannabinoid levels at a time when mice develop paclitaxel-induced mechanical allodynia. We also evaluated the peripheral antiallodynic activity of the endocannabinoid 2-arachidonoyl glycerol (2-AG) and an inhibitor of monoacylglycerol lipase (MAGL), an enzyme responsible for 2-AG hydrolysis. METHODS: Female BALB/c mice were treated intraperitoneally with paclitaxel to induce mechanical allodynia. Levels of the endocannabinoids, N-arachidonoylethanolamine (anandamide, AEA), 2-AG, and the N-acylethanolamines (NAEs), N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), which are structurally-related to AEA, in the brain, spinal cord and paw skin were measured using LC-MS/MS. Protein expression of MAGL in the paw skin was measured using Wes™. The effects of subcutaneous (s.c.) injection of 2-AG and JZL184 (a MAGL inhibitor) into the right hind paw of mice with paclitaxel-induced mechanical allodynia were assessed using the dynamic plantar aesthesiometer. The effects of pretreatment, s.c., into the right hind paw, with cannabinoid type 1 (CB1) receptor antagonist AM251 and CB2 receptor antagonist AM630 on the antiallodynic effects of 2-AG were also evaluated. RESULTS: The levels of 2-AG were reduced only in the paw skin of paclitaxel-treated mice, whilst the levels of AEA, PEA and OEA were not significantly altered. There was no change in the expression of MAGL in the paw skin. Administration of 2-AG and JZL184 produced antiallodynic effects against paclitaxel-induced mechanical allodynia in the injected right paw, but did not affect the uninjected left paw. The antiallodynic activity of 2-AG was antagonized by both AM251 and AM630. CONCLUSION: These results indicate that during paclitaxel-induced mechanical allodynia there is a deficiency of 2-AG in the periphery, but not in the CNS. Increasing 2-AG in the paw by local administration of 2-AG or a MAGL inhibitor, alleviates mechanical allodynia in a CB1 and CB2 receptor-dependent manner. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/32603895/Peripheral_deficiency_and_antiallodynic_effects_of_2_arachidonoyl_glycerol_in_a_mouse_model_of_paclitaxel_induced_neuropathic_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(20)30649-1 DB - PRIME DP - Unbound Medicine ER -