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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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Related in: MedlinePlus

Effects of URB597 and WIN 55,212-2 treatment over seven days on below-level cutaneous hypersensitivity in rats with neuropathic SCI pain.Baseline hind paw withdrawal thresholds were measured prior to treatment with either URB597 (3 mg/kg, i.p.), WIN 55,212-2 (3 mg/kg, s.c.) or vehicle (Veh, 1.5 ml/kg, i.p.). Rats were treated twice daily and tested following the first daily injection. On the first day of testing, a robust antinociception was observed beginning 30 min post-injection of WIN 55,212-2, which was observed also observed on days 3 and 7. By contrast, no antinociceptive effects were observed following treatment with either URB597 or vehicle. Data presented as mean ± S.E.M. n = 8–10/group. * p<0.05 vs. vehicle (Two-way repeated measures ANOVA, Student-Newman-Keuls test).
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pone-0096396-g006: Effects of URB597 and WIN 55,212-2 treatment over seven days on below-level cutaneous hypersensitivity in rats with neuropathic SCI pain.Baseline hind paw withdrawal thresholds were measured prior to treatment with either URB597 (3 mg/kg, i.p.), WIN 55,212-2 (3 mg/kg, s.c.) or vehicle (Veh, 1.5 ml/kg, i.p.). Rats were treated twice daily and tested following the first daily injection. On the first day of testing, a robust antinociception was observed beginning 30 min post-injection of WIN 55,212-2, which was observed also observed on days 3 and 7. By contrast, no antinociceptive effects were observed following treatment with either URB597 or vehicle. Data presented as mean ± S.E.M. n = 8–10/group. * p<0.05 vs. vehicle (Two-way repeated measures ANOVA, Student-Newman-Keuls test).

Mentions: Prior to seven day dosing, the mean hind paw withdrawal threshold of all SCI rats was 3.9±0.6 g (Fig. 6). The mean baseline withdrawal thresholds, within each treatment group, prior to the morning treatment, did not significantly change over the seven day treatment period (p>0.05). Significant increases in withdrawal thresholds were observed 30 min following treatment with WIN 55,212-2 on each day of behavioral testing. In fact, on each day of testing, WIN 55,212-2 fully ameliorated hind paw cutaneous hypersensitivity (p<0.05 vs. vehicle treatment and vs. baseline; two-way repeated measures-ANOVA). Furthermore, on each of the testing days the effect persisted for the duration of the four hour testing period. By contrast, URB597 did not significantly increase withdrawal thresholds at any time post-treatment (p>0.05 vs. vehicle treatment). Likewise, vehicle treatment did not significantly alter withdrawal thresholds.


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)

Effects of URB597 and WIN 55,212-2 treatment over seven days on below-level cutaneous hypersensitivity in rats with neuropathic SCI pain.Baseline hind paw withdrawal thresholds were measured prior to treatment with either URB597 (3 mg/kg, i.p.), WIN 55,212-2 (3 mg/kg, s.c.) or vehicle (Veh, 1.5 ml/kg, i.p.). Rats were treated twice daily and tested following the first daily injection. On the first day of testing, a robust antinociception was observed beginning 30 min post-injection of WIN 55,212-2, which was observed also observed on days 3 and 7. By contrast, no antinociceptive effects were observed following treatment with either URB597 or vehicle. Data presented as mean ± S.E.M. n = 8–10/group. * p<0.05 vs. vehicle (Two-way repeated measures ANOVA, Student-Newman-Keuls test).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0096396-g006: Effects of URB597 and WIN 55,212-2 treatment over seven days on below-level cutaneous hypersensitivity in rats with neuropathic SCI pain.Baseline hind paw withdrawal thresholds were measured prior to treatment with either URB597 (3 mg/kg, i.p.), WIN 55,212-2 (3 mg/kg, s.c.) or vehicle (Veh, 1.5 ml/kg, i.p.). Rats were treated twice daily and tested following the first daily injection. On the first day of testing, a robust antinociception was observed beginning 30 min post-injection of WIN 55,212-2, which was observed also observed on days 3 and 7. By contrast, no antinociceptive effects were observed following treatment with either URB597 or vehicle. Data presented as mean ± S.E.M. n = 8–10/group. * p<0.05 vs. vehicle (Two-way repeated measures ANOVA, Student-Newman-Keuls test).
Mentions: Prior to seven day dosing, the mean hind paw withdrawal threshold of all SCI rats was 3.9±0.6 g (Fig. 6). The mean baseline withdrawal thresholds, within each treatment group, prior to the morning treatment, did not significantly change over the seven day treatment period (p>0.05). Significant increases in withdrawal thresholds were observed 30 min following treatment with WIN 55,212-2 on each day of behavioral testing. In fact, on each day of testing, WIN 55,212-2 fully ameliorated hind paw cutaneous hypersensitivity (p<0.05 vs. vehicle treatment and vs. baseline; two-way repeated measures-ANOVA). Furthermore, on each of the testing days the effect persisted for the duration of the four hour testing period. By contrast, URB597 did not significantly increase withdrawal thresholds at any time post-treatment (p>0.05 vs. vehicle treatment). Likewise, vehicle treatment did not significantly alter withdrawal thresholds.

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