Peripheral deficiency and antiallodynic effects of 2-arachidonoyl glycerol in a mouse model of paclitaxel-induced neuropathic pain

Autor: Bright N. Okine, Amal Thomas, Willias Masocha, David P. Finn
Rok vydání: 2020
Předmět:
0301 basic medicine
Cannabinoid receptor
medicine.medical_treatment
Monoacylglycerol lipase
Pharmacology
Receptor
Cannabinoid
CB2
chemistry.chemical_compound
0302 clinical medicine
Piperidines
Receptor
Cannabinoid
CB1
Cannabinoid receptor type 2
2-Arachidonoyl glycerol
Enzyme Inhibitors
JZL184
Skin
Analgesics
Mice
Inbred BALB C
General Medicine
Allodynia
Hyperalgesia
030220 oncology & carcinogenesis
Neuropathic pain
lipids (amino acids
peptides
and proteins)
Female
medicine.symptom
medicine.drug
AM251
Paclitaxel
RM1-950
Arachidonic Acids
Glycerides
03 medical and health sciences
medicine
Animals
Benzodioxoles
Cannabinoid receptors
Endocannabinoid
Cannabinoid Receptor Agonists
Monoacylglycerol Lipases
Disease Models
Animal
030104 developmental biology
chemistry
Chemotherapy-induced neuropathic pain
Neuralgia
Cannabinoid
Therapeutics. Pharmacology
Endocannabinoids
Zdroj: Biomedicine & Pharmacotherapy, Vol 129, Iss, Pp 110456-(2020)
ISSN: 1950-6007
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: