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The Journal of Neuroscience, December 20, 2006, 26(51):13318-13327; doi:10.1523/JNEUROSCI.3326-06.2006

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Neurobiology of Disease
Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Maulik D. Jhaveri,¹ Denise Richardson,² David A. Kendall,¹ David A. Barrett,² and Victoria Chapman¹

¹School of Biomedical Sciences, Medical School, Queens Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, United Kingdom, and ²School of Pharmacy, University of Nottingham, Nottinghamshire NG7 2RD, United Kingdom

Correspondence should be addressed to Dr. Maulik D. Jhaveri, School of Biomedical Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, UK. Email: maulik.jhaveri{at}nottingham.ac.uk

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 µg in 50 µl) 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 µg in 50 µl) 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 µg in 50 µl) 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 µg in 50 µl) 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.

Key words: electrophysiology; endocannabinoid; spinal nerve ligation; URB597; CB₁ receptor; opioid receptor

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Received March 24, 2006; revised Oct. 31, 2006; accepted Nov. 16, 2006.

Correspondence should be addressed to Dr. Maulik D. Jhaveri, School of Biomedical Sciences, Medical School, Queen's Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, UK. Email: maulik.jhaveri{at}nottingham.ac.uk

Related articles in J. Neurosci.:

Inhibition of Fatty Acid Amide Hydrolase: A Potential Treatment for Neuropathic Pain

Tuan Trang
J. Neurosci. 2007 27: 3364-3365. [Full Text]  

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