Cytokine inhibition and time-related influence of inflammatory stimuli on the hyperalgesia induced by the nucleus pulposus

Abstract

Introduction The symptoms of lumbar disc herniation, such as low back pain and sciatica, have been associated with local release of cytokines following the inflammatory process induced by the contact of the nucleus pulposus (NP) with the spinal nerve. Material and methods Using an animal experimental model of intervertebral disc herniation and behavioral tests to evaluate mechanical (electronic von Frey test) and thermal (Hargreaves Plantar test) hyperalgesia in the hind paw of rats submitted to the surgical model, this study aimed to detect in normal intervertebral disc the cytokines known to be involved in the mechanisms of inflammatory hyperalgesia, to observe if previous exposure of the intervertebral disc tissue to specific antibodies could affect the pain behavior (mechanical and thermal hyperalgesia) induced by the NP, and to observe the influence of the time of contact of the NP with the fifth lumbar dorsal root ganglion (L5-DRG) in the mechanical and thermal hyperalgesia. Results The cytokines present at highest concentrations in the rat NP were TNF-a, IL-1b and CINC-1. Rats submitted to the disc herniation experimental model, in which a NP from the sacrococcygeal region is deposited over the right L5-DRG, showed increased mechanical and thermal hyperalgesia that lasted at least 7 weeks. When the autologous NP was treated with antibodies against the three cytokines found at highest concentrations in the NP (TNF-a, IL-1b and CINC-1), there was decrease in both mechanical and thermal hyperalgesia in different time points, suggesting that each cytokine may be important for the hyperalgesia in different steps of the inflammatory process. The surgical remotion of the NP from herniated rats 1 week after the implantation reduced the hyperalgesia to the level similar to the control group. This reduction in the hyperalgesia was also observed in the group that had the NP removed 3 weeks after the implantation, although the intensity of the hyperalgesia did not decreased totally. The removal of the NP after 5 weeks did not changed the hyperalgesia observed in the hind paw, which suggests that the longer the contact of the NP with the DRG, the greater is the possibility of development of chronic pain. Conclusion Together our results indicate that specific cytokines released during the inflammatory process induced by the herniated intervertebral disc play fundamental role in the development of the two modalities of hyperalgesia (mechanical and thermal) and that the maintenance of this inflammation may be the most important point for the chronification of the pain.

Effects of degenerative autologous nucleus pulposus on the lumbar sympathetic trunk: Sympathetic inflammation in rats

“…The radicular pain associated with posterior herniation of the lumbar intervertebral discs has been extensively investigated. Inflammatory responses induced by the leakage of the NP from the posterior herniation of a lumbar disc have been confirmed to be the main reason for radicular pain [4,14,15] . The sympathetic trunk is apposed to the anterior surface of the spine, leaving it vulnerable to insult associated with NP leakage caused by the herniation.…”

“…Andrade et al [3] reported that IL-1 β and IL-6 can be secreted by discs biopsies from LDH patients; de Souza et al [4] reported that the rat disc can secrete the highest concentrations of IL-1 and TNF-α. Zhang et al [13] also reported significant increase in the expression of TNF-α positive neurons in DRG.…”

“…Neuro-inflammation, instead of pure mechanical compression, may underlie the pathophysiology of radicular pain, and the maintenance of this neuroinflammation may be the most important mechanism for the chronification of radicular pain [2] . Neuroinflammation induced by the contact of the nucleus pulposus (NP) with the spinal nerve has been accepted as a cause for radicular pain [3,4] . An epidural steroid injection that can reduce neuro-inflammation is one of the most commonly used treatments for radiculopathy [5] .…”

The Michel Benoist and Robert Mulholland yearly European Spine Journal Review

“…In the March issue de Souza Grava et al [8] describe an experimental animal model aiming to detect the presence of inflammatory cytokines in a normal intervertebral disc in rats. The second objective was to investigate whether a previous exposure of the IVD tissue by specific anti-cytokine antibodies could modify the pain behaviour induced by application of nucleus pulposus (NP) on the L5-RDG in rats.…”

Análise do envelhecimento e degeneração de discos intervertebrais humanos cervicais e lombares

“…Hoyland et al 192 apontem com bastante segurança que a IL-1β é mais importante no processo de degeneração do DIV, e que experimentos utilizando o seu inibidor (IL1Ra) 30,36,131 tenham alcançado relativo sucesso terapêutico, o TNF-α não parece ter apenas um papel determinante no tecido durante o envelhecimento e degeneração 37 , mas também é apontado como a citocina mais catabólica e anti-anabólica no tecido discal 177 , além de atuar na origem da dor discogênica através da desmielinização ou inflamação dos terminais nervosos do DIV 20,29,177,193 . Desta forma, considerando-se os resultados acerca da IL-1β, pode-se afirmar que a mesma é secundária nesse processo, uma vez que foi diferenciada apenas no setor anterior desses espécimes.…”