Tags

Type your tag names separated by a space and hit enter

The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice.
Br J Pharmacol. 2012 Apr; 165(8):2485-96.BJ

Abstract

BACKGROUND AND PURPOSE

Inflammatory pain presents a problem of clinical relevance and often elicits allodynia, a condition in which non-noxious stimuli are perceived as painful. One potential target to treat inflammatory pain is the endogenous cannabinoid (endocannabinoid) system, which is comprised of CB1 and CB2 cannabinoid receptors and several endogenous ligands, including anandamide (AEA). Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without the psychomimetic side effects associated with Δ(9) -tetrahydrocannabinol (THC).

EXPERIMENTAL APPROACH

Allodynia was induced by intraplantar injection of LPS. Complementary genetic and pharmacological approaches were used to determine the strategy of blocking FAAH to reverse LPS-induced allodynia. Endocannabinoid levels were quantified using mass spectroscopy analyses.

KEY RESULTS

FAAH (-/-) mice or wild-type mice treated with FAAH inhibitors (URB597, OL-135 and PF-3845) displayed an anti-allodynic phenotype. Furthermore, i.p. PF-3845 increased AEA levels in the brain and spinal cord. Additionally, intraplantar PF-3845 produced a partial reduction in allodynia. However, the anti-allodynic phenotype was absent in mice expressing FAAH exclusively in the nervous system under a neural specific enolase promoter, implicating the involvement of neuronal fatty acid amides (FAAs). The anti-allodynic effects of FAAH-compromised mice required activation of both CB1 and CB2 receptors, but other potential targets of FAA substrates (i.e. µ-opioid, TRPV1 and PPARα receptors) had no apparent role.

CONCLUSIONS AND IMPLICATIONS

AEA is the primary FAAH substrate reducing LPS-induced tactile allodynia. Blockade of neuronal FAAH reverses allodynia through the activation of both cannabinoid receptors and represents a promising target to treat inflammatory pain.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21506952

Citation

Booker, Lamont, et al. "The Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-3845 Acts in the Nervous System to Reverse LPS-induced Tactile Allodynia in Mice." British Journal of Pharmacology, vol. 165, no. 8, 2012, pp. 2485-96.
Booker L, Kinsey SG, Abdullah RA, et al. The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. Br J Pharmacol. 2012;165(8):2485-96.
Booker, L., Kinsey, S. G., Abdullah, R. A., Blankman, J. L., Long, J. Z., Ezzili, C., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2012). The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. British Journal of Pharmacology, 165(8), 2485-96. https://doi.org/10.1111/j.1476-5381.2011.01445.x
Booker L, et al. The Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-3845 Acts in the Nervous System to Reverse LPS-induced Tactile Allodynia in Mice. Br J Pharmacol. 2012;165(8):2485-96. PubMed PMID: 21506952.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. AU - Booker,Lamont, AU - Kinsey,Steven G, AU - Abdullah,Rehab A, AU - Blankman,Jacqueline L, AU - Long,Jonathan Z, AU - Ezzili,Cyrine, AU - Boger,Dale L, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, PY - 2011/4/22/entrez PY - 2011/4/22/pubmed PY - 2012/7/28/medline SP - 2485 EP - 96 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 165 IS - 8 N2 - BACKGROUND AND PURPOSE: Inflammatory pain presents a problem of clinical relevance and often elicits allodynia, a condition in which non-noxious stimuli are perceived as painful. One potential target to treat inflammatory pain is the endogenous cannabinoid (endocannabinoid) system, which is comprised of CB1 and CB2 cannabinoid receptors and several endogenous ligands, including anandamide (AEA). Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without the psychomimetic side effects associated with Δ(9) -tetrahydrocannabinol (THC). EXPERIMENTAL APPROACH: Allodynia was induced by intraplantar injection of LPS. Complementary genetic and pharmacological approaches were used to determine the strategy of blocking FAAH to reverse LPS-induced allodynia. Endocannabinoid levels were quantified using mass spectroscopy analyses. KEY RESULTS: FAAH (-/-) mice or wild-type mice treated with FAAH inhibitors (URB597, OL-135 and PF-3845) displayed an anti-allodynic phenotype. Furthermore, i.p. PF-3845 increased AEA levels in the brain and spinal cord. Additionally, intraplantar PF-3845 produced a partial reduction in allodynia. However, the anti-allodynic phenotype was absent in mice expressing FAAH exclusively in the nervous system under a neural specific enolase promoter, implicating the involvement of neuronal fatty acid amides (FAAs). The anti-allodynic effects of FAAH-compromised mice required activation of both CB1 and CB2 receptors, but other potential targets of FAA substrates (i.e. µ-opioid, TRPV1 and PPARα receptors) had no apparent role. CONCLUSIONS AND IMPLICATIONS: AEA is the primary FAAH substrate reducing LPS-induced tactile allodynia. Blockade of neuronal FAAH reverses allodynia through the activation of both cannabinoid receptors and represents a promising target to treat inflammatory pain. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21506952/The_fatty_acid_amide_hydrolase__FAAH__inhibitor_PF_3845_acts_in_the_nervous_system_to_reverse_LPS_induced_tactile_allodynia_in_mice_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01445.x DB - PRIME DP - Unbound Medicine ER -