Establishment and Characterization of a Novel Rat Model of Mechanical Low Back Pain Using Behavioral, Pharmacologic and Histologic Methods

Abstract

Chronic low back pain (LBP), the leading cause of disability globally, is notoriously difficult to treat. Most rodent models of LBP mimic lumbar radicular pain rather than mechanical LBP. Here, we describe establishment of a new rat model of mechanical LBP that is devoid of a neuropathic component. Groups of adult male Sprague Dawley rats were anesthetized and their lumbar L4/L5 and L5/L6 intervertebral disks (IVDs) were punctured (0.5 mm outer diameter, 2mm-deep) 5 (LPB-5X), or 10 (LBP-10X) times per disk. Sham-rats underwent similar surgery, but without disk puncture. Baseline noxious pressure hyperalgesia of lumbar axial deep tissues, mechanical allodynia in the hindpaws and gait were assessed prior to surgery and once-weekly until study completion on day 49. The model was also characterized using pharmacologic and histologic methods. Good animal health was maintained for ≥ 49 days post-surgery. For LBP- but not sham-rats, there was temporal development of noxious pressure hyperalgesia in lumbar axial deep tissues at days 14–49 post-surgery. Importantly, there were no between-group differences in von Frey paw withdrawal thresholds or gait parameters until study completion. On day 49, significant histologic changes were observed in the L4/L5 and L5/L6 IVDs for LBP-10X rats, but not sham-rats. In LBP-10X rats, single bolus doses of morphine produced dose-dependent relief of primary and secondary mechanical hyperalgesia in lumbar axial deep tissues at L4/L5 and L1, respectively. In conclusion, our new rat model has considerable potential for providing novel insight on the pathobiology of mechanical LBP and for analgesic efficacy assessment of novel compounds.

Icariin Ameliorates Lower Back Pain in Rats via Suppressing the Secretion of Cytokine-Induced Neutrophil Chemoatractant-1

“…Two-way ANOVA and Tukey's multiple comparison test were used for statistical analysis). [9,15]. Moreover, SP and CGRP, direct pain-related peptides, acted as the "biomarkers" of pain, which was in accordance with behavioral assessment, further validating LBP in rodents.…”

“…Here, the IVDs at L4~5 and L5~6 were punctured with an 18-gauge needle based on a previous report to establish the LBP model [15]. The puncture would directly alter the mechanical properties of the IVDs, thus causing damage to the annulus fibrosus and an increase in cytokines [16], which finally caused IVD degeneration and discogenic LBP [10].…”

The Somatostatin Receptor-4 Agonist J-2156 Alleviates Mechanical Hypersensitivity in a Rat Model of Breast Cancer Induced Bone Pain

“…Based on the animal ethics principle of “Reduction,” a “washout protocol” was used such that each rat received up to a maximum of four individual intraperitoneal (i.p.) doses of J-2156 or vehicle with at least 2–3 days of “washout” between successive doses as per the common practice in pain research (Zeppetella et al, 2003 ; Kim et al, 2010 ; Otto et al, 2011 ; Varamini et al, 2012 ; Muralidharan et al, 2013 , 2017 ; Han et al, 2014 ; Khan et al, 2014 ; Otis et al, 2016 ; Friton et al, 2017a , b ; Shenoy et al, 2017 ; Suzuki et al, 2017 ). The animals that received a new treatment on a different occasion after the washout period, were cumulatively added to build the “n” numbers.…”

“…All other graphs were stored, represented and analyzed using the GraphPad Prism TM (v7.00) software. The ED50 values were calculated as per the method described previously (Rowlett et al, 1999 ; Muralidharan et al, 2013 , 2017 ; Han et al, 2014 ; Khan et al, 2014 ; Shenoy et al, 2017 ). The change in the PWT values (ΔPWT) in the hindpaws of rats following administration of single bolus doses of J-2156 or vehicle was determined by subtracting the predosing PWT values from the respective post-dosing PWT values for individual rats at each time-point i.e.,…”

Assessment of the anti‐hyperalgesic efficacy of J‐2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP)

“…However, its efficacy in a mild to moderate rat model of chronic mechanical LBP remains to be assessed. Hence, the aims of our research herein were (a) to assess the face validity of our previously reported LBP‐5X rat model of mild to moderate cLBP 16 using clinically available analgesic/adjuvant agents and, (b) to assess the anti‐hyperalgesic efficacy of single bolus doses of J‐2156 in our LBP‐5X rat model of mild to moderate chronic mechanical LBP.…”