Highlights
- •Inhibiting the soluble epoxide hydrolase (sEH) is effective against neuropathic pain.
- •sEH inhibitors are effective against chronic pain in an operant nociceptive assay.
- •The small molecule sEH inhibitors show potent analgesia without reward side effects.
Abstract
Neuropathic pain is currently an insufficiently treated clinical condition. There
remains a critical need for efficacious therapies without severe side effects to treat
the uniquely persistent and tonic pain of neuropathy. Inhibitors of the soluble epoxide
hydrolase (sEH) enzyme that stabilize endogenous epoxy fatty acids have demonstrated
antihyperalgesia in clinical chronic inflammatory pain and modeled neuropathic pain.
Recently, the conditioned place preference assay has been used to evaluate the tonic
nature of neuropathy in several animal models. The current experiments use the conditioned
place preference assay alongside withdrawal thresholds to investigate the antihyperalgesic
efficacy of sEH inhibitors in a murine model of diabetic neuropathy. Here, the sEH
inhibitor trans-4-[4-(3-trifluoromethoxyphenyl-1-ureido)-cyclohexyloxy]-benzoic acid (t-TUCB) at 10 mg/kg induced a robust place preference in diabetic neuropathic mice
representative of pain relief. Importantly, this effect was absent both in control
mice and in sEH-knockout mice at the same dose, indicating that t-TUCB is not positively reinforcing or rewarding. When compared to gabapentin, t-TUCB elicited a similar degree of withdrawal threshold improvement without the same
degree of spontaneous locomotion decline in neuropathic mice. Overall, these experiments
show that inhibiting the sEH enzyme attenuates chronic pain and offers an alternative
to current side-effect-limited therapies to meet this clinical need.
Perspective
These experiments demonstrate antihyperalgesia in a murine chronic pain model mediated
by inhibiting the sEH enzyme. The results of this study indicate that inhibiting the
sEH is a promising alternative for blocking chronic pain.
Key words
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Article info
Publication history
Published online: June 10, 2014
Accepted:
May 28,
2014
Received in revised form:
May 10,
2014
Received:
November 15,
2013
Footnotes
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
This work was supported by the National Institute of Environmental Health Sciences (NIEHS) Grant R01 ES002710 (to B.D.H.), NIEHS Superfund Research Program P42 ES004699, National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases R21AR062866 and Grants National Institute of Environmental Health Sciences T32ES007059 and NIH 5T32DC008072-05 (to K.W.).
The University of California holds patents on the sEH inhibitors used in this study as well as their use to treat inflammation, inflammatory pain, and neuropathic pain. B.D.H. and B.I. are cofounders of Eicosis L.L.C., a startup company advancing sEH inhibitors into the clinic. K.W. and J.Y. have no conflicts of interest.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Foundation.
Identification
Copyright
© 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
