Anesth Pain Med.  2019 Jan;14(1):76-84. 10.17085/apm.2019.14.1.76.

Analgesic effects of soluble epoxide hydrolase inhibitor in K/BxN serum transfer arthritis mouse model

• Park J
• Cho MJ
• Ha G
• Park HJ

• KMID: 2434203
• DOI: http://doi.org/10.17085/apm.2019.14.1.76

Abstract

BACKGROUND
Soluble epoxide hydrolase (sEH) is an enzyme that converts epoxyeicosatrienoic acid (EET) into the anti-inflammatory dihydroxyeicosatrienoic acids (DHET). Inhibition of sEH by the potent soluble epoxide hydrolase inhibitor (sEHI) decreases inflammation by increasing EET. The K/BxN serum transfer mouse model of arthritis displays an initial inflammation and an associated tactile allodynia that continues on following the resolution of inflammation.
METHODS
We undertook the following studies: i) Using the K/BxN mouse model, we examined effects on allodynia during the early inflammatory phase of administration of sEHI 3 mg/kg and/or diclofenac (DFC) 10 mg/kg. ii) In the late inflammatory phase, we administered sEHI (3, 10, or 30 mg/kg); DFC 10 mg/kg; gabapentin 100 mg/kg. iii) Using the conditioned place preference (CPP) we examined the synergism between sEHI and DFC in the K/BxN mouse using the CPP paradigm. The drug was administered intraperitoneally and the allodynia was measured with the von Frey test.
RESULTS
In the early phase, both sEHI and DFC displayed an antiallodynic action. In the late phase, sEHI, and gabapentin but not DFC were effective in reversing the allodynia. Comparable results were observed with the CPP.
CONCLUSIONS
This study demonstrates that sEHI reduces mechanical allodynia in both the early and the late inflammatory K/BxN mouse model of arthritis. The sEHI target thus addresses the hyperalgesia arising from inflammation as well as the post-inflammatory phase that has been said to reflect neuropathic-like states, thus presenting alternatives to the limited efficacy of arthritis drugs in use.

Keyword

Analgesic effect; K/BxN serum transfer arthritis mouse model; Soluble epoxide hydrolase inhibitor

MeSH Terms

Animals
Arthritis*
Diclofenac
Hyperalgesia
Inflammation
Mice*
Diclofenac

Figure

• 

  Fig. 1 (A) Clinical signs of arthritis, including digital redness and swelling. The clinical score starts on day 2 and shows the most severe change on day 6. (B) Mechanical allodynia in arthritic mice. Significant changes occur on day 5 and remain until day 28.

• 

  Fig. 2 (A) When soluble epoxide hydrolase inhibitor (sEHI) is administered in the early phase of the arthritis model, the paw withdrawal threshold (PWT) increases significantly over 180 minutes and peaks at 60 minutes. This result is similar to the diclofenac (DFC) group. The group that received both sEHI and DFC shows the most significant PWT change (P < 0.0001) at all time points. (B) The area under the curve (AUC) shows that DFC, sEHI, and DFC + sEHI increase in order (*P < 0.050, †P < 0.001, ‡P < 0.0001).

• 

  Fig. 3 (A) In the late phase, no significant difference is shown among the control, diclofenac (DFC), soluble epoxide hydrolase inhibitor (sEHI) 3 mg/kg, and sEHI 3 mg/kg + DFC 10 mg/kg groups (P > 0.050). A significant difference is present in the sEHI 30 mg/kg group at 30, 60, and 120 minutes, with the most significant difference at 60 minutes (P < 0.0001). (B) In the area under the curve (AUC), the sEHI 30 mg/kg + DFC 10 mg/kg group shows the greatest value. (C) In the maximal possible effect (MPE), the sEHI + DFC combination group is more effective than the sEHI alone group over the entire dose (*P < 0.050, †P < 0.010, ‡P < 0.001, ¦P < 0.0001).

• 

  Fig. 4 (A) In the early phase, the diclofenac (DFC), soluble epoxide hydrolase inhibitor (sEHI), and DFC + sEHI groups show differences in the mean value of the adaptation days and the test days compared to the vehicle group. (B) In the late phase, the sEHI and DFC + sEHI groups differ in the mean value of the adaptation day and the mean value of the test day (P < 0.050). The DFC alone group, however, shows no difference compared to the vehicle group. CPP: conditioned place preference, Veh: vehicle, D: DFC, S: sEHI.

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