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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.

Hama AT, Germano P, Varghese MS, Cravatt BF, Milne GT, Pearson JP, Sagen J - PLoS ONE (2014)

Bottom Line: 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.Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.

View Article: PubMed Central - PubMed

Affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

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.

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Fatty acid amide concentrations in lumbar spinal cord from SCI rats or uninjured rats following treatment with FAAH inhibitors, WIN 55,212-2 and vehicle.Rats were treated with either URB597 (URB; 3 mg/kg, i.p.), WIN 55,212-2 (WIN; 3 mg/kg, s.c.) or vehicle (Veh; 1.5 ml/kg, i.p.) for seven days and euthanized four hours following the last treatment. One group of uninjured rats was treated once with URB597 and euthanized two hours (2 h) following treatment. Rats that received PF-3845 (PF3, PF10) were treated once (3, 10 mg/kg, p.o.) and euthanized four hours following dosing. Levels of AEA, OEA and PEA from each rat are shown, the thick horizontal line is the mean and the thin horizontal lines are the S.E.M. n = 4–10/group. * p<0.05, **p<0.01, ***p<0.001 vs. vehicle (Student's t-test).
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pone-0096396-g005: Fatty acid amide concentrations in lumbar spinal cord from SCI rats or uninjured rats following treatment with FAAH inhibitors, WIN 55,212-2 and vehicle.Rats were treated with either URB597 (URB; 3 mg/kg, i.p.), WIN 55,212-2 (WIN; 3 mg/kg, s.c.) or vehicle (Veh; 1.5 ml/kg, i.p.) for seven days and euthanized four hours following the last treatment. One group of uninjured rats was treated once with URB597 and euthanized two hours (2 h) following treatment. Rats that received PF-3845 (PF3, PF10) were treated once (3, 10 mg/kg, p.o.) and euthanized four hours following dosing. Levels of AEA, OEA and PEA from each rat are shown, the thick horizontal line is the mean and the thin horizontal lines are the S.E.M. n = 4–10/group. * p<0.05, **p<0.01, ***p<0.001 vs. vehicle (Student's t-test).

Mentions: Analyses of LC-MS/MS data were conducted using GraphPad Prism software. For FAA, statistical comparisons between treatment groups were made using an unpaired, two-tailed Student's t-test. To determine fold-change in levels of FAA, the levels were normalized to the respective vehicle-treated group. p values less than 0.05 were considered significant. To assess the effect of treatment over time on behaviors, a two-way repeated measures analysis of variance (ANOVA) was performed with Student-Newman-Keuls for post hoc analysis. Fatty acid amide levels from each rat were plotted (Fig. 1–5) and the mean ± S.E.M. were calculated. Behavioral data are presented as mean ± S.E.M.


Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.

Hama AT, Germano P, Varghese MS, Cravatt BF, Milne GT, Pearson JP, Sagen J - PLoS ONE (2014)

Fatty acid amide concentrations in lumbar spinal cord from SCI rats or uninjured rats following treatment with FAAH inhibitors, WIN 55,212-2 and vehicle.Rats were treated with either URB597 (URB; 3 mg/kg, i.p.), WIN 55,212-2 (WIN; 3 mg/kg, s.c.) or vehicle (Veh; 1.5 ml/kg, i.p.) for seven days and euthanized four hours following the last treatment. One group of uninjured rats was treated once with URB597 and euthanized two hours (2 h) following treatment. Rats that received PF-3845 (PF3, PF10) were treated once (3, 10 mg/kg, p.o.) and euthanized four hours following dosing. Levels of AEA, OEA and PEA from each rat are shown, the thick horizontal line is the mean and the thin horizontal lines are the S.E.M. n = 4–10/group. * p<0.05, **p<0.01, ***p<0.001 vs. vehicle (Student's t-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008577&req=5

pone-0096396-g005: Fatty acid amide concentrations in lumbar spinal cord from SCI rats or uninjured rats following treatment with FAAH inhibitors, WIN 55,212-2 and vehicle.Rats were treated with either URB597 (URB; 3 mg/kg, i.p.), WIN 55,212-2 (WIN; 3 mg/kg, s.c.) or vehicle (Veh; 1.5 ml/kg, i.p.) for seven days and euthanized four hours following the last treatment. One group of uninjured rats was treated once with URB597 and euthanized two hours (2 h) following treatment. Rats that received PF-3845 (PF3, PF10) were treated once (3, 10 mg/kg, p.o.) and euthanized four hours following dosing. Levels of AEA, OEA and PEA from each rat are shown, the thick horizontal line is the mean and the thin horizontal lines are the S.E.M. n = 4–10/group. * p<0.05, **p<0.01, ***p<0.001 vs. vehicle (Student's t-test).
Mentions: Analyses of LC-MS/MS data were conducted using GraphPad Prism software. For FAA, statistical comparisons between treatment groups were made using an unpaired, two-tailed Student's t-test. To determine fold-change in levels of FAA, the levels were normalized to the respective vehicle-treated group. p values less than 0.05 were considered significant. To assess the effect of treatment over time on behaviors, a two-way repeated measures analysis of variance (ANOVA) was performed with Student-Newman-Keuls for post hoc analysis. Fatty acid amide levels from each rat were plotted (Fig. 1–5) and the mean ± S.E.M. were calculated. Behavioral data are presented as mean ± S.E.M.

Bottom Line: 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.Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.

View Article: PubMed Central - PubMed

Affiliation: Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

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.

Show MeSH
Related in: MedlinePlus