Korean J Pain.  2014 Jul;27(3):219-228. 10.3344/kjp.2014.27.3.219.

Therapeutic Effect of Epidurally Administered Lipo-Prostaglandin E1 Agonist in a Rat Spinal Stenosis Model

• Park SH
• Lee PB
• Choe GY
• Moon JY
• Nahm FS
• Kim YC

• KMID: 2278226
• DOI: http://doi.org/10.3344/kjp.2014.27.3.219

Abstract

BACKGROUND
A lipo-prostaglandin E1 agonist is effective for the treatment of neurological symptoms of spinal stenosis when administered by an oral or intravenous route. we would like to reveal the therapeutic effect of an epidural injection of lipo-prostaglandin E1 on hyperalgesia in foraminal stenosis.
METHODS
A total of 40 male Sprague-Dawley rats were included. A small stainless steel rod was inserted into the L5/L6 intervertebral foramen to produce intervertebral foraminal stenosis and chronic compression of the dorsal root ganglia (DRG). The rats were divided into three groups: epidural PGE1 (EP) (n = 15), saline (n = 15), and control (n = 10). In the EP group, 0.15 microg.kg-1 of a lipo-PGE1 agonist was injected daily via an epidural catheter for 10 days from postoperative day 3. In the saline group, saline was injected. Behavioral tests for mechanical hyperalgesia were performed for 3 weeks. Then, the target DRG was analyzed for the degree of chromatolysis, chronic inflammation, and fibrosis in light microscopic images.
RESULTS
From the fifth day after lipo-PGE1 agonist injection, the EP group showed significant recovery from mechanical hyperalgesia, which was maintained for 3 weeks (P < 0.05). Microscopic analysis showed much less chromatolysis in the EP group than in the saline or control groups.
CONCLUSIONS
An epidurally administered lipo-PGE1 agonist relieved neuropathic pain, such as mechanical hyperalgesia, in a rat foraminal stenosis model, with decreasing chromatolysis in target DRG. We suggest that epidurally administered lipo-PGE1 may be a useful therapeutic candidate for patients with spinal stenosis.

Keyword

epidural administration; hyperalgesia; spinal stenosis

MeSH Terms

Alprostadil
Animals
Catheters
Constriction, Pathologic
Diagnosis-Related Groups
Fibrosis
Ganglia, Spinal
Humans
Hyperalgesia
Inflammation
Injections, Epidural
Male
Neuralgia
Rats*
Rats, Sprague-Dawley
Spinal Stenosis*
Stainless Steel
Alprostadil
Stainless Steel

Figure

• 

  Fig. 1 Flowchart of the study. A lipo-PGE1 agonist was injected daily for 10 days from postoperative day 3. In the saline group, normal saline was injected in the same way. Behavioral tests for mechanical hyperalgesia were performed for 3 weeks. Then, the microscopic analysis was performed. For microscopic examination, all rats were sacrificed on day 3 after completion of the behavioral observations, which was the 24th day after the final drug administration. (A) Preoperative behavioral test was performed. (B) Operation day; modeling was done. (C) Postoperative day 3; behavioral test was done immediately before drug administration and then the first dose of drug was administered. (D) Postoperative day 4; 1 day after the first drug administration. (E) Postoperative day 9; 5 days after the first drug administration. (F) Postoperative day 14; 10 days after the first drug administration and the day of the final drug administration. (G) Postoperative day 21; 1 week after the last drug administration. (H) Postoperative day 28; 2 weeks after the last drug administration. (I) Postoperative day 35; 3 weeks after the last drug administration and last behavioral test was performed. (J) Postoperative day 38; sacrifice at 3 days after the last behavioral study and the 24th day after the final drug administration. (X) Postoperative days 3-13; lipo-PGE1 or normal saline was administered daily for 10 days.

• 

  Fig. 2 Characteristic histological changes in the DRG. (A) Both central and segmental chromatolysis is noted. (B) Note central chromatolysis in the center. Most of the cytoplasm appears homogeneous, and the powdery remains of the Nissl substance are confined to the periphery of the neuron. (C) Note segmental chromatolysis, which shows globular segmental loss of Nissl substance (H&E staining ×400). *: central chromatolysis, ▾: segmental chromatolysis.

• 

  Fig. 3 Grade of the epidural fibrosis. Grade 1: Loose fibrosis, focal. Grade 2: Loose fibrosis, diffuse (> 50%). Grade 3: Dense fibrosis, focal. Grade 4: Dense fibrosis, diffuse (> 50%). The histological degree of fibrosis was graded by the extent and intensity of collagen fibers detected by Masson's trichome staining (×400).

• 

  Fig. 4 Grade of chronic inflammation. Grade 0: Absent. Grade 1: One view of at least five inflammatory cells. Grade 2: More than one view of grade 1 or at least one view of 5-20 inflammatory cells. Grade 3: Multiple and/or confluent grade 2. Grade 4: Diffuse and dense inflammation (H&E staining ×400).

• 

  Fig. 5 Changes in mechanical hyperalgesia. From the 10th day after lipo-PGE1 agonist injection, the EP group showed significant recovery of the mechanical threshold, which was maintained for 3 weeks. The EP group received an epidural injection of lipo-PGE1 after the operation in a rat foraminal stenosis model. The saline group received an epidural injection of normal saline after the operation in a rat foraminal stenosis model. The control group did not receive an epidural injection after the operation in a rat foraminal stenosis model. Data are mean ± standard error of the mean (SEM) (%). *P < 0.05 EP group vs. NS or control group. Before means before the operation. Baseline means before epidural injection of the test drugs.

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