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Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain
Open accessAbstract
Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve ligation or sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30 microg in 50 microl) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of sham-operated rats. Intraplantar URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.
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“In the same study, spinal administration of URB597 was equally efficacious at attenuating mechanically-evoked responses and increasing levels of endogenous cannabinoids in SNL and sham rats and these effects were CB1-mediated.92”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [92]
In the citing paper
“The antinociceptive effects of URB597 were blocked by a CB1-specific antagonist in both sham and SNL rats.92”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [92]
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“Low doses of locally injected URB597 (i.pl.) reduced mechanically-evoked responses of WDR neurons and increased endocannabinoid levels in ipsilateral paw tissue of sham operated rats.92”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [92]
In the citing paper
“A four-fold higher dose was required for reduction of mechanically-evoked WDR neuronal responses in SNL rats; these rats showed no corresponding increase in endocannabinoid levels, suggesting that contributions of FAAH to endocannabinoid metabolism may be modified under conditions of neuropathic nociception.92”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [92]
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Cites
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Research works printed but not linked: 1
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Targeting the endocannabinoid system: to enhance or reduce?
Marzo, V. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2553 · Cited by 822
Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system
Schlosburg, J. E., Blankman, J. L., Long, J. Z., Nomura, D. K., Pan, B., Kinsey, S. G., Nguyen, P. T., Ramesh, D., Booker, L., Burston, J. J., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2616 · Cited by 641
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The Endocannabinoid System and Pain
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Metadata
- Authors
- Jhaveri, M. D., Richardson, D., Kendall, D. A., Barrett, D. A., & Chapman, V.
- Affiliations
- University of Nottingham (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-12-20
- Volume
- 26
- Issue
- 51
- Pages
- 13318-13327
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6674985
- OpenAlex
- W2037393750
- Cited by
- 159
- References
- 76
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 9 · 2012: 14
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- Directorate for Biological Sciences
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- fatty acid amide hydrolase inhibition, neuropathic pain, spinal nerve ligation, URB597, endocannabinoids, anandamide, 2-arachidonoylglycerol, oleoylethanolamide, cannabinoid 1 receptor, AM251, naloxone, mechanical nociception, spinal cord neurons, analgesia
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Analgesics, Animals, Benzamides, Carbamates, Disease Models, Animal, Enzyme Inhibitors, Injections, Spinal, Male, Pain, Pain Measurement, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Rats
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