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ASP8477, a fatty acid amide hydrolase inhibitor, exerts analgesic effects in rat models of neuropathic and dysfunctional pain.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2020 Aug 15; Vol. 881, pp. 173194. Date of Electronic Publication: 2020 May 21. - Publication Year :
- 2020
-
Abstract
- Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E <subscript>2</subscript> -, prostaglandin F <subscript>2α</subscript> -, and bicuculline-induced allodynia in mice, showing broader analgesic spectra than existing drugs. In contrast, however, ASP8477 did not affect acute pain. These results indicate that the FAAH inhibitor ASP8477 exerts analgesic effects on neuropathic and dysfunctional pain, and its pharmacological properties are suitable for use in treating chronic pain.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Amides metabolism
Amidohydrolases metabolism
Analgesics pharmacokinetics
Animals
Behavior, Animal drug effects
Brain enzymology
Brain physiopathology
Chronic Pain enzymology
Chronic Pain physiopathology
Disease Models, Animal
Enzyme Inhibitors pharmacokinetics
Ethanolamines metabolism
Male
Neuralgia enzymology
Neuralgia physiopathology
Oleic Acids metabolism
Pain Threshold drug effects
Palmitic Acids metabolism
Piperidines pharmacokinetics
Pyridines pharmacokinetics
Rats, Sprague-Dawley
Amidohydrolases antagonists & inhibitors
Analgesics pharmacology
Brain drug effects
Chronic Pain drug therapy
Enzyme Inhibitors pharmacology
Neuralgia drug therapy
Piperidines pharmacology
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 881
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32445705
- Full Text :
- https://doi.org/10.1016/j.ejphar.2020.173194