The utility of ionotropic glutamate receptor antagonists in the treatment of nociception induced by epidural glutamate infusion in rats.

BACKGROUND: The authors have previously demonstrated that human herniated disc material contains high concentrations of free glutamate. In an experimental model, elevated epidural glutamate concentrations in the lumbar spine can cause a focal hyperesthetic state. METHODS: Rats underwent epidural glutamate infusion in the lumbar spine by a miniosmotic pump over a 72-hour period. Some rats underwent coinfusion with glutamate and ionotropic glutamate antagonists. Nociception was assessed by von Frey fibers and by assessment of glutamate receptor expression in the corresponding dorsal horn of the spinal cord. RESULTS: The kainic acid antagonist, UBP 301, decreased epidural glutamate-based hyperesthesia in a dose dependent manner. Concordant with these findings, there was significant decrease in kainate receptor expression in the dorsal horn. The N-Methyl-4-isoxazoleproionic acid (NMDA) antagonist Norketamine also significantly diminished hyperesthesia and decreased receptor expression in the dorsal horn. CONCLUSIONS: Both UBP 301, the kainic acid receptor antagonist and Norketamine, an NMDA receptor antagonist, dampened epidural glutamate-based nociception. Focal epidural injections of Kainate or NMDA receptor antagonists could be effective treatments for disc herniation-based lumbar radiculopathy.

Radiographic predictors of delayed instability following decompression without fusion for degenerative grade I lumbar spondylolisthesis.

OBJECT: It is not known whether adding fusion to lumbar decompression is necessary for all patients undergoing surgery for degenerative lumbar spondylolisthesis with symptomatic stenosis. Determining specific radiographic traits that might predict delayed instability following decompression surgery might guide clinical decision making regarding the utility of up-front fusion in patients with degenerative Grade I spondylolisthesis. METHODS: Patients with Grade I degenerative lumbar spondylolisthesis (3-14 mm) with symptomatic stenosis were prospectively enrolled from a single site between May 2002 and September 2009 and treated with decompressive laminectomy without fusion. Patients with mechanical back pain or with gross motion (> 3 mm) on flexion-extension lumbar radiographs were excluded. The baseline radiographic variables measured included amount of slippage, disc height, facet angle, motion at spondylolisthesis (flexion-extension), and sagittal rotation angle. Data were analyzed using multivariate forward selection stepwise logistic regression, chi-square tests, Student t-test, and ANOVA. RESULTS: Forty patients were enrolled and treated with laminectomy without fusion, and all patients had complete radiographic data sets that were available for analysis. Reoperation was performed in 15 (37.5%) of 40 patients, with a mean follow-up duration of 3.6 years. Reoperation was performed for pain caused by instability at the index level in all 15 cases. Using multivariate stepwise logistic regression with a threshold p value of 0.35, motion at spondylolisthesis, disc height, and facet angle were predictors of reoperation following surgery. Facet angle > 50° was associated with a 39% rate of reoperation, disc height > 6.5 mm was associated with a 45% rate of reoperation, and motion at spondylolisthesis > 1.25 mm was associated with a 54% rate of reoperation. Patients with all 3 risk factors for instability had a 75% rate of reoperation, whereas patients with no risk factors for instability had a 0% rate of reoperation (p = 0.14). CONCLUSIONS: Patients with motion at spondylolisthesis > 1.25 mm, disc height > 6.5 mm, and facet angle > 50° are more likely to experience instability following decompression surgery for Grade I lumbar spondylolisthesis. Identification of key risk factors for instability might improve patient selection for decompression without fusion surgery.

Excrescence of neurotransmitter glutamate from disc material has nociceptive qualities: evidence from a rat model.

BACKGROUND CONTEXT: The authors have previously demonstrated that herniated human lumbar disc is rich in free glutamate from degradation of aggrecan. Prior data have suggested that free glutamate could contribute to a nociceptive state. PURPOSE: Previous behavioral experiments suggested glutamate-related nociception by comparing pre- and postglutamate infusion responses only. This indirectly suggested nociceptive effects of epidural glutamate but was not a definitive evidence. Now, by using larger numbers of subjects, we have demonstrated that lumbar epidural glutamate infusion causes significant left-to-right differences in hind paw response during treatment, demonstrating more directly the focal nociceptive effects of glutamate. STUDY DESIGN: Behavioral studies and immunohistochemistry were used to assess for evidence of a nociceptive state. All researchers were blinded to infusion solution. METHODS: Via an implanted mini osmotic pump, the epidural space of rats was infused with 0.02 mM glutamate or normal saline for 72 hours. Signs of nociception were assessed by von Frey and plantar thermal stimulation testing and by glutamate receptor expression in the corresponding dorsal horn of the spinal cord and dorsal root ganglion. RESULTS: Both von Frey mechanical and plantar thermal stimulations showed differences in hind paw reactivity depending on whether it was on the ipsilateral or contralateral side of glutamate infusion. Saline infusion had no significant behavioral effects. Dorsal horn expression of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid and N-methyl-d-aspartic acid receptors was significantly increased in glutamate-infused animals, further indicative of a nociceptive state related to glutamate infusion. CONCLUSIONS: Elevated epidural glutamate concentrations caused a focal hyperesthetic state. Increased epidural glutamate concentration could be a driving force or "chemical" component of disc-related radiculopathy.

Shedding of tumor necrosis factor type 1 receptor after experimental spinal cord injury.

In a number of stress conditions, the biological effects of tumor necrosis factor-alpha (TNF-alpha), such as the induction of neuronal apoptosis, are presumably attenuated by the soluble fragments of TNF receptors (sTNFRs). Within 1 h after spinal cord injury, increased synthesis and/or secretion of TNF-alpha is detectable at the injury site. However, the shedding of ectodomains of TNFRs in the traumatized spinal cord has not yet been reported. In the present study, adult Sprague-Dawley rats were subjected to acute spinal cord injury (ASCI) by applying a 25-g Walsh-Tator aneurysm clip at the C8-T1 level. Sham-injured animals underwent laminectomy and facetectomy only. A PE10 catheter was placed in the subarachnoid space to collect the samples of cerebrospinal fluid (CSF) from near the injury site. These CSF samples were analyzed by ELISA for the presence of TNF-alpha and soluble TNFR1 and TNFR2 (sTNFR1 and sTNFR2, respectively). The spinal cord tissue was analyzed by immunohistochemistry for the expression of TNF-alpha, TNFR1, and TNFR2, and by the TUNEL technique for the occurrence of neuronal death. The levels of TNFR1 and sTNFR1 in the injured tissue were determined by Western blotting. Immunohistochemistry demonstrated the increased neuronal expression of TNF-alpha and its receptors at 6 h post-ASCI. No changes in the intensity of staining were observed in the sham-injured rats. In addition, at 6 h after the injury, a significant increase in the number of TUNEL-positive neurons was observed. Numerous neurons in traumatized tissue were also immunoreactive for activated caspase-3, suggesting that the TUNEL-positive neurons were undergoing an apoptotic death. At 1 h after ASCI, TNF-alpha levels in the CSF were significantly higher than those found in the sham-injured animals, indicating the release of this cytokine into the interstitial fluid. This was followed by a significant increase, compared to the sham-injured controls, in sTNFR1 levels in the CSF at 3 and 6 h after the insult. Unlike sTNFR1, the levels of sTNFR2 in the CSF were unchanged at any time point post-ASCI. The increased shedding of TNFR1 was confirmed by Western blotting. It is concluded that the shedding of TNFR1 receptor may represent an important post-traumatic physiological response aimed at reducing the proapoptotic effect of TNF-alpha.

Physiological and behavioral evidence for focal nociception induced by epidural glutamate infusion in rats.

STUDY DESIGN: Blinded animal study. OBJECTIVES: To determine if an increased concentration of epidural glutamate can cause a focal nociceptive response in the lower extremities that is consistent with sciatica. SUMMARY OF BACKGROUND DATA: It is believed that the origin of sciatic pain is related to more than physical pressure on the nerve roots. Recently, it was determined that disc material may be a significant source of free glutamate, resulting from the enzymatic degradation of matrix aggrecan proteins. We believe that this free glutamate acts as a neurotransmitter at glutamate receptors on the dorsal root ganglion (DRG) cell bodies, thereby initiating a nociceptive response. METHODS: Rats were subject to a 72-hour epidural glutamate infusion via a mini osmotic pump. Von Frey behavioral testing was performed 24 hours before, and 24 and 72 hours after the onset of the infusion. DRG and dorsal horn tissues were analyzed for changes in receptor expression, which have been previously shown to correlate with a nociceptive state. RESULTS: Von Frey behavioral tests showed focal hyperalgesia that was maximal at the 0.02 mmol/L glutamate concentration. Significant changes in DRG glutamate receptor expression were seen for alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid, kainite, and N-methyl-D aspartate receptors. Analysis of dorsal horn glutamate receptors also showed patterns in alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid and kainate receptor expression that were consistent with a nociceptive state. CONCLUSIONS: Epidural glutamate elicits a focal nociceptive response. Free glutamate that has been liberated from the disc material may be an important factor in the development of sciatic pain.