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Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.
PLoS One 2014; 9(5):e96396Plos

Abstract

Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.

Authors+Show Affiliations

Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24788435

Citation

Hama, Aldric T., et al. "Fatty Acid Amide Hydrolase (FAAH) Inhibitors Exert Pharmacological Effects, but Lack Antinociceptive Efficacy in Rats With Neuropathic Spinal Cord Injury Pain." PloS One, vol. 9, no. 5, 2014, pp. e96396.
Hama AT, Germano P, Varghese MS, et al. Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain. PLoS ONE. 2014;9(5):e96396.
Hama, A. T., Germano, P., Varghese, M. S., Cravatt, B. F., Milne, G. T., Pearson, J. P., & Sagen, J. (2014). Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain. PloS One, 9(5), pp. e96396. doi:10.1371/journal.pone.0096396.
Hama AT, et al. Fatty Acid Amide Hydrolase (FAAH) Inhibitors Exert Pharmacological Effects, but Lack Antinociceptive Efficacy in Rats With Neuropathic Spinal Cord Injury Pain. PLoS ONE. 2014;9(5):e96396. PubMed PMID: 24788435.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain. AU - Hama,Aldric T, AU - Germano,Peter, AU - Varghese,Matthew S, AU - Cravatt,Benjamin F, AU - Milne,G Todd, AU - Pearson,James P, AU - Sagen,Jacqueline, Y1 - 2014/05/02/ PY - 2014/02/04/received PY - 2014/04/07/accepted PY - 2014/5/3/entrez PY - 2014/5/3/pubmed PY - 2015/6/24/medline SP - e96396 EP - e96396 JF - PloS one JO - PLoS ONE VL - 9 IS - 5 N2 - Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24788435/Fatty_acid_amide_hydrolase__FAAH__inhibitors_exert_pharmacological_effects_but_lack_antinociceptive_efficacy_in_rats_with_neuropathic_spinal_cord_injury_pain_ L2 - http://dx.plos.org/10.1371/journal.pone.0096396 DB - PRIME DP - Unbound Medicine ER -