Inhibition of fatty acid amide hydrolase unmasks CB1receptor and TRPV1 channel‐mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey
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BACKGROUND AND PURPOSE: While arachidonyl ethanolamine (anandamide) produces pharmacological effects mediated by cannabinoid CB1 receptors, it is also an agonist at the transient receptor potential vanilloid type 1 (TRPV1) ion channel. This study examined the cellular actions of anandamide in the midbrain periaqueductal grey (PAG), a region implicated in the analgesic actions of cannabinoids, and which expresses both CB1 receptors and TRPV1. EXPERIMENTAL APPROACH: In vitro whole cell patch clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) were made from rat and mouse PAG slices. KEY RESULTS: Capsaicin (1 µM) increased the rate, but not the amplitude of miniature EPSCs in subpopulations of neurons throughout the rat and mouse PAG. Capsaicin had no effect on miniature EPSCs in PAG neurons from TRPV1 knock-out mice. In mouse PAG neurons, anandamide (30 µM) had no effect on the rate of miniature EPSCs alone, or in the presence of either the CB1 antagonist AM251 (3 µM) or the TRPV1 antagonist iodoresiniferatoxin (300 nM). Anandamide produced a decrease in miniature EPSC rate in the presence of the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 µM). By contrast, anandamide produced an increase in miniature EPSC rate in the presence of both URB597 and AM251, which was absent in TRPV1 knock-out mice. CONCLUSIONS AND IMPLICATIONS: These results suggest that the actions of anandamide within PAG are limited by enzymatic degradation by FAAH. FAAH blockade unmasks both presynaptic inhibition and excitation of glutamatergic synaptic transmission which are mediated via CB1 receptors and TRPV1 respectively.
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There is evidence of presynaptic expression of TRPV1 in the nucleus tractus solitarus and periaqueductal grey.
“There is also evidence of presynaptic expression of TRPV1 in the nucleus tractus solitarus and PAG (Kawahara et al., 2011).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Kawahara et al., 2011
Available evidence suggests that effects at TRPV1 are in opposition to the anti-anxiety-like behavioral actions exerted through CB1R.
“As the available evidence suggests that effects at TRPV1 appear to be in opposition to the (anti-anxiety-like) behavioral actions exerted through CB1R (Kawahara et al., 2011)”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Kawahara et al., 2011
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- Authors
- Kawahara, H., Drew, G., Christie, M., & Vaughan, C.
- Affiliations
- The University of Sydney (AU)
- Corresponding author
- Kawahara, H
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2011-06-27
- Volume
- 163
- Issue
- 6
- Pages
- 1214-1222
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3144535
- OpenAlex
- W1514108563
- Cited by
- 67
- References
- 56
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 4 · 2015: 3 · 2014: 10 · 2013: 6 · 2012: 7
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council
- National Medical Research Council
- 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
- anandamide, fatty acid amide hydrolase, CB1 receptor, TRPV1, periaqueductal gray, glutamatergic neurotransmission, presynaptic inhibition, capsaicin, URB597, AM251, cannabinoid analgesia, excitatory postsynaptic currents
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Capsaicin, Female, Male, Mice, Inbred C57BL, Synaptic Transmission, Periaqueductal Gray, Rats, Sprague-Dawley, Mice, Knockout, Receptor, Cannabinoid, CB1, TRPV Cation Channels, Mice, Rats, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids
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