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Neural-Immune Interactions: Implications for Pain Management in Patients with Low-Back Pain and Sciatica Angela Starkweather, PhD, ACNP, RN Linda Witek-lanusek, RN, PhD I I erbert L. Mathews, PhD Bidirectional communication between the immune enced health problems in the United States and is the system and the brain and the implications ofthis com- 2nd most frequent condition, after the common cold, munication are emerging concepts in pain research. for which people see a physician or lose days from Although representing a small portion of the disc work. Low-back pain and sciatica are common and degeneration syndromes, lumbar herniated discs can debilitating conditions that produce significant burden cause significant symptoms that maypersist even after in terms of human suffering and financial cost. It is surgical interventions. Evolving evidence demon- estimated that direct medical costs associated with strates thatproinflammatory cytokines are a key medi- these conditions exceed $25 billion annually (Casey ator in the process of disc degeneration as well as in 1995). Because of physical impairment and psycho- the pain experienced by those afflicted with lumbar logical morbidity, the personal impact of low-back herniated discs. Activated immune cells release pain and sciatica on quality of life is immense (Turk proinflammatory cytokines, which signal the brain and Gatchel 2002). through humoral and neural routes. The brain Biomechanical compression of the nerve root by a responds by altering neural activity and promoting herniated disc has traditionally been considered to be further production of pminfiammatory cytokines the sole pathogenic factor for inducing sciatica. How- within the brain and spinal cord. Increased local ever, because sciatica may be present in the absence of cytokine production by disc tissue irritates spinal disc herniation (Olmarker and Hause 1995; Wood and nerve roots, resulting in pain andfunctional changes in neural activity. This review of the current literature explores the importance ofcytokine production within Angela Starkweather, PhD, ACNP, RN, is an assistant pro- the context of lumbar disc degeneration and lumbar lessor in theIntercollegiate College ofNursing. Washington spine pain. Furthermore, the significance of the State University, Spokane. Linda IVitek-lanusek, RN, PhD, neural-immune interaction will be examined as it is a professor ofacute, chronic, and long-term care nursing and Herbert L Mathews, PhD, is a professor ofMicrobiol- relates to pain management and to patient treatment. ogy and Immunology at Loyola University, Chicago, Illi- Key words: proinflammatory cytokines, nucleus nois. Address for correspondence: Angela Starkweather, pulposus, lumbar herniated disc, disc degeneration Washington State University, Intercollegiate College of Nursing, 2917 West For George Wright Drive, Room 369, Back pain remains an elusive clinical problem. Low- Spokane, WA 99224; phone: 509.324.7279; e-mail: [email protected]. back pain is considered one of the most widely experi- BIOLOGICAL RESEARCH FOR NURSING The authors would like to acknowledge thefollowing agen- Vol. 6. No. 3. January 2005. 196-206 ciesfor their support: Illinois Emergency Nurses Associa- DOI: '0.1I7M09980010427222I tion, Sigma Theta Thu Alpha Beta Chapter, and the Neuro- Copyright 0 2005 Sage Publications science Nursing Foundation. EFTA00308035  Starkweather and others / Neural-Immune Interactions 197 others 1997) and the size of herniation does not corre- acestne mecturacal shear stress on late with pain indices (Kawakami and others 1996, disc tissue 1997), other biological mechanisms of sciatic pain are now considered plausible. Recently, molecules se- NeovascuLtrization.ingi wth of Activation is IMP raises creted by immune cells (i.e., cytokines) have been im- sectary naves into disc endpInes increased ma n dcgathaion with net loss of protcoglycant plicated in pain transmission, and compelling new evi- dence (primarily in animal models) demonstrates a role for proinflammatory cytokines in the evolution Disc degeneration and low back pain and progression of low-back pain and sciatica (Watkins and Maier 2000; Watkins and others 2003). With continued loss of proteopyrarts and continued mechanical shear stress, the disc is at Understanding the influences of local cytokine pro- peace risk of .101111bf tears and herniation duction and its impact on perceived pain may lead to novel approaches that can improve the quality of life e Disc 'amanita. among patients with disc herniation and sciatic pain. ,.„,. I Methodology A literature search was performed using the Ovid search engine within the categories of nursing, medi- cine, biology, microbiology, and cellular biology. Direct mechanical >simulation and ft0}111/.1000 of the dorsal 1001 Sanshon Nets Nuckus pulpotus induced nem injury met damage ..., 1 ......, Altered biochemical environment of the IVD •-•-• • . : Local release of Neat red d sfunctico: Nets I001lariat poollartunnay crazies motor weakness. saucily Manuscripts were limited to the English language but changes Immune cells infiltrate to the site and release were not limited by date of publication. Review and re- poollanarnauxygtokmes and chemokines search articles related to disc herniation in animal models and human studies were included. PIDIMAMCIllOrf cytokines implicated in ppm& but not peosen • Prosnflamnutory cytokines inmate and prolong process Mechanisms of Disc Degeneration and Direct sensory acne amnion Nontraumatic Herniation Disc degeneration is the initial process leading to Figure 1. Mechanisms of disc degeneration and non- nontraumatic disc herniation (see Fig. 1). This theoret- traumatic herniation. MMP = metalloproteinases; 1VD = ical pathway describes the biomechanical and bio- intervertebral disc tissue. chemical events responsible for the process of disc ag- ing, or degeneration, which ultimately leads to the experience of pain phenomena (low-back pain and sci- atica). Traditionally, it has been believed that the dis- Mechanical Shear Stress placed disc tissue was a by-product of the disease and not an interactive element in the disease process itself. The function of the intervertebral disc is to provide However, the discovery of elevated levels of the spine with mobility while retaining axial stability proinflammatory cytokines within injured disc tissue (Greenberg 2001). Although physiologic loading by Takahashi and colleagues (1996) led researchers to helps to maintain metabolism and function in conceptualize it as a biologically active tissue. Since intervertebral discs, excessive mechanical loading ap- that time, connections between the immune system, pears to be detrimental. Certain occupations pose a nervous system, and pain behavior in disc injury have hazard to the rate of disc degeneration. Those occupa- continued to evolve. The current understanding of the tions that entail repetitive bending, twisting, and lift- mechanisms of disc degeneration and nontraumatic ing from the trunk and expose workers to whole-body herniation will be reviewed inrelationship to Figure 1. vibration have a higher propensity to accelerate disc EFTA00308036 198 BIOLOGICAL RESEARCH FOR NURSING Vol. 6. No. 1 January 2005 degeneration (Bovendi 1996; Damkot and others MMPs (van Den Berg 1999). Thus, there is growing 1984). However, Elfervig and others (2001) found evidence of the role of proinflammatory cytokines in other factors that influence the effect of mechanical matrix degradation (disc degeneration), nerve and loading on disc degeneration. In their study, treating vessel ingrowth, and pain. discs with interleukin (IL)-10, a proinflammatory There is mounting evidence that immune factors are cytokine known to stimulate production of metallo- involved not only in the initiation of disc degeneration proteinases (MMPs), sensitized annulus cells to me- but also in the progression of disc disease. As the in- chanical loading. This effect renders annulus cells jured disc tissue continues to produce elevated levels more susceptible to injury from excessive load, caus- of MMPs, thereby losing proteoglycans, the diseased ing the progression of disc degeneration through stim- tissue begins to wear down. Annular tears form along ulating production of MMPs that degrade matrix, in- the outer wall of the disc, making it more susceptible cluding proteoglycans. Studies have demonstrated to splitting, and thus herniating, in the face of that loss of proteoglycans is one of the main biochemi- exertional forces that raise the intervertebral pressure cal changes in the annulus of degenerative discs, mak- (Benoist 2002). ing them susceptible to annulus tears and herniation When a herniated disc does occur, it produces an (Stevens and others 1982; Benoist 2002). autoimmune inflammatory response resulting in the production of a variety of pain-producing substances. Neovascularization These are produced not only by infiltrating inflamma- tory cells but also by histiocytes, fibroblasts, endothe- Nerve ingrowth into the degenerate lumbar lial cells, and chondrocytes of the disc itself. Such intervertebral disc has been well documented findings support the concept that disc-associated (Palmgren and others 1996; Coppes and others 1997). proinflammatory substances may be a major factor in Freemont and colleagues (1997) demonstrated an as- the creation of sciatic pain. The current findings of sociation between nerve ingrowth and the patient's ex- disc herniation in animal models and human studies perience of pain. These nerves had the characteristics will be reviewed to determine how these mechanisms and markers of actively growing nonmyelinated pain affect health outcomes and how they may translate into fibers, with substance P as the neurotransmitter. In new therapies to prevent and manage the degenerated 2002, Freemont, Watkins, Le Maitre, Baird, and others or herniated disc. discovered that small nonmyelinated nerve fibers grow into the intervertebral disc only in areas where Direct Mechanical Stimulation and there is local production of the neurotrophic factor Sensitization of the Dorsal Root Ganglion NGE NGF is produced by microvessels, which populate the normally avascular (and aneural) Dislocation of intervertebral disc tissue (IVD) by intervertebral disc by extension from adjacent bone. nucleus pulposus (NP) protrusion or extrusion (i.e., Their study provides compelling evidence that this herniated disc) is a common source of severe pain. pattern of nerve growth and receptor expression is im- Herniation of the NP causes it to contact and compress plicated in the innervation of painful tissues through the dorsal root ganglion (DRG) and spinal root that en- NGF-driven axonal growth and maturation. ters the spine at the vertebral level. Acute mechanical The stimulus that promotes microvessels to release compression is sufficient to produce spontaneous ac- NGF, triggering the process of nerve and vessel tivity in the sensory afferents, supporting the classic ingrowth, remains uncertain. However, IL-1 is cur- assumption that mechanical compression is the cause rently being investigated because it is involved in carti- of pain and other neurological symptoms. Mechanical lage homeostatis (Cawston and others 1999). IL-1 has compression has been thought to account for the the ability to switch chondroctyes from anabolism to ischemia, edema, and demyelination that occur in the catabolism, inducing cartilage breakdown at molecu- DRG and the pain that may arise from nerve endings in lar and morphological levels through stimulating the outer annulus fibrosus. Olmarker and Myers EFTA00308037  Starkweather and others / Neural-Immune Interactions 199 (1998) used a rat model of disc herniation to verify NP-Induced Nerve Injury these hypotheses. In the 1st subset of animals, air was injected into the NP and transferred to theL,nerve root Pathological pain can arise as a consequence of the and DRG. The 2nd subset underwent displacement of protrusion of the NP into contact with the DRG and the DRG. The 3rd subset had both disc herniation and dorsal root. Although pressure per se has classically the displacement procedure completed while the sham been considered as a major cause of pain, there is subset underwent exposure of the spinal canal only. growing evidence that immune-derived substances Compared to animals receiving the sham protocol, the may be involved as well. Diverse immune cells and reduction in mechanical threshold was statistically equally diverse immune cell products are potential significant in the combination protocol (disc mediators. Of these, proinflammatory cytokines have herniation with DRG displacement) at days 2, 4, 16, received by far the most attention. Data to date suggest and 18. The combination group also showed a marked a strong case in support of proinflammatory cytokine reduction in the thermal latency of the left (operated) involvement in the pain of herniated discs. The side compared to the contralateral side by 2 days cytokines may do this by inducing expression of re- postprocedure that was not normalized until 14 days ceptors within DRGs. Also, axonal interactions with postprocedure. Histologically, the nerve roots from proinflammatory cytokines could increase electrical the 1st subset demonstrated mild edema. The displace- conductivity. Each of these could then lead to painful ment group demonstrated more severe edema of the stimuli. DRG, and the combination group demonstrated Olmarker and others (1993) used autologous NP edema, endothelial and Schwann cell hypertrophy, harvested from the intervertebral disc in hogs and demyelinization, and widespread myelin abnormali- placed it epidurally, in close contact with the spinal ties at postprocedure day 21. This study demonstrated nerve roots. The control group had fat placed in the that displacement of the DRG alone (similar to me- same fashion. Electromyelogram studies were used to chanical compression) causes edema of the DRG and measure nerve velocities at 1 day (84 ± 2 control; 63 ± minor changes in motor function; however, with 9 NP), 3 days (83 ±4 control; 45 ± 16 NP), and 7 days simultaneous disc herniation, there is severe cellular (76 ± 11 control; 45 ± 19 NP) postimplantation. There breakdown and significant changes in sensory was a significant reduction of nerve velocities in the function. NP group at all time points. Histological examination Pain behavior was observed by Olmarker and others of the nerve fibers exposed to NP revealed axonal (2002) using the same protocol. A single technician swelling, increased axoplasmic density, splitting of blindly assessed the video recordings of the rats during the myelin sheaths, and swelling and attenuation of the a 20-min interval the day after surgery, 2 weeks after Schwann cell cytoplasm that worsened subsequently surgery, and 3 weeks after surgery. In those with both at each time point, whereas there were no histological disc incision and displacement, there was increased changes in the fat group. This study suggests the pres- focal pain, seen as increased lifting of the hind paw on ence of a biochemical substance in the NP that causes the operated side and increased rotation of the head to- dysfunction in the nerve root and ongoing ward the operated side, as compared with the sham deterioration of nerve root morphology over time. group. There were no significant differences in behav- Otani and others (1997) evaluated nerve conduction ior between the groups at day 14. However, 3 weeks velocities (NCVs) in a dog model of disc herniation. after surgery, there was another pattern of increased NCV was measured in normal dogs as control. The immobility and decreased locomotion in the combina- sham group had theL, nerve root retracted for 10 s and tion group as compared with the sham group. Unfortu- replaced. The herniation group had the same proce- nately, the authors did not include measurements of dure completed with the addition of 0.01 mL of saline nerve injury or proinflammatory cytokines, which injected into the center of the disc with visible leakage would have provided insight into the biochemical and of NP into the spinal canal. Both groups were assessed functional sequelae of mechanical stimulation and at I, 3, and 7 days postprocedure. The NCVs in the sensitization of the DRG. sham groups were stable at about 70 m/s. The NCVs in EFTA00308038 200 BIOLOGICAL RESEARCH FOR NURSING Vol. 6. No. 1 January 2005 the herniation groups started to decline at day 3 (61 ± tail in rats and applied to the L,, nerve root just proxi- 14 m/s) and reached a maximum reduction after 7 days mal to the DRG, whereas muscle was used in the (39 ± 24 m/s), which was statistically significant. control group. DRG blood flow was measured using a ICayama and others (1998) also demonstrated func- laser Doppler flowmeter before application. Blood tional changes in spinal nerve roots through applica- flow in the NP group was significantly decreased (by tion of NP. In this study, harvested NP and skin were 12% and 19%) compared to the muscle group at both 3 cultured for 3 weeks. Culture medium, conditioned and 4 h postapplication. EFP was recorded with a culture medium, dead autologous fibroblasts, live servo-null micropipette system attached to the con- autologous fibroblasts, dead autologous NP cells, and nective tissue membrane surrounding the DRG. There live autologous NP cells were applied to the cauda was a statistically significant increase in EFP in the NP equina in the same pigs, respectively, from which the group. Histologically, the DRG in the muscle group cells were harvested. One week postapplication, nerve appeared normal, whereas in the NP group, there was conduction velocities were recorded. The mean nerve edema, endothelial cell activation, and myelin disrup- conduction velocities in the live fibroblasts and condi- tion. The results of this study demonstrate the role of tioned culture medium series were slightly lower than NP in initiating local change in blood flow and in the those in the control dead fibroblast series, but they inflammatory process that characterizes disc were not significant. However, the dead and live NP herniation. cells series demonstrated a statistically significant re- The relationship between blood flow and motor duction. The authors concluded that the functional nerve conduction velocity was examined by Otani and changes must be induced by a membrane-related others (1999). Annulus fibrosus of the L64 structure of the NP cells or bioactive substances, such intervertebral disc in canine models were incised and as cytokines. punctured by an 18-gauge needle. NP was pushed into Takebayashi and colleagues (2001) surgically ex- the epidural space near the L, nerve root. The sham posed the L3 dorsal root in rats and implanted either group underwent exposure of the L1 nerve root only. autologous NP or autologous fat as an implantation Intraneural blood flow in the nerve root was measured control. Using electmphysiologic techniques, the with a tissue blood flowmeter using the electrolytic spontaneous discharge rate of the L,, DRG was mea- hydrogen clearance method. Motor NCV was deter- sured at 30-min intervals for 6 hours after implanta- mined by stimulating the left L, nerve root using an tion. A significant increase in the spontaneous dis- electronic stimulator and recording muscle action po- charge rate (SDR) was continuously observed from tentials in the gastrocnemius muscle. There was a re- 150 min to the end of the recording (360 min) in the an- duction of the intraneural blood flow in the nerve root imals that were implanted with autologous NP. No after 1-day post—disc incision that was statistically sig- change in SDR was noted in the animals that received nificant when compared with a sham group of animals. autologous fat. In addition, mechanosensitivity of the The NCV began to be reduced 3 days after disc inci- DRG was measured before application and every 2 h sion and was statistically significant on day 7, whereas using calibrated nylon filaments. Six hours after appli- the sham group demonstrated normal NCV through- cation, the mechanical thresholds in the NP group re- out the testing period. The authors concluded that the mained statistically elevated from those of the fat reduction of the nerve root blood flow is one important group. This study supports the hypothesis that sciatica pathophysiologic mechanism for NP-induced nerve can result from exposure of the NP to the nerve root, injury. which caused excitation and mechanical hypersensitivity in the DRG without mechanical Biochemical Mediators compression. in Herniated Disc Tissue Yabuki and others (1998) demonstrated more spe- cific effects on the DRG by measuring blood flow and Neuropathic pain can occur as a consequence of endoneurial fluid pressure (EFP) after application of nerve trauma, with physical damage to nerves altering NP. Autologous NP was harvested from the amputated pain perception and the function of pain transmission EFTA00308039  Starkweather and others / Neural-Immune Interactions 201 pathways. However, neuropathic pain can also occur pain-producing molecules. It also demonstrated that in the absence of any detectable physical injury. In the biochemical mechanisms of the intervertebral disc these situations, pathological pain appears to be a con- are vulnerable to the influences of biologic stimuli, sequence of immune activation and inflammation, and it illuminated a mechanism of disc degeneration. which can also amplify pain as a consequence of phys- Induction of MMPs leads to excessive breakdown of ical trauma. The role of immune activation in the disc matrix, whereas nitric oxide, IL-6, and PGE, neuropathic conditions has been firmly established, impair matrix synthesis. and a consistent picture has emerged from these mod- Miyamoto and others (2000) analyzed herniated els of traumatic and/or inflammatory neuropathic lumbar discs for the presence of IL-1P, TNF-a and pain. The key cellular mediators are most likely cyclooxygenase (COX)-2, which induces the synthe- inflammatory cells recruited into the affected area sis of PGE, during inflammation. The authors com- from the general circulation along with locally stimu- pared herniated specimens with normal discs obtained lated cell populations. These cells produce from patients undergoing anterior lumbar fusion for proinflammatory cytokines (tumor necrosis factor traumatic burst fracture. Their results demonstrated [TNF], IL-1, IL-6) within the affected area and create that COX-2, IL-1P, and TNF-ot are present within the and maintain pathological pain. cytosol of the chondrocytes constituting the lumbar Takahashi and colleagues (1996) led one of the first disc in all herniated specimens but not in any samples investigations that used human specimens acquired of normal disc tissue. When chondrocytes of the herni- during surgery. The tissue adjacent to the nerve roots at ated disc were stimulated with IL-14i, a remarkable in- the herniation was excised and analyzed for the pres- crease in the production of PGE, was observed. Al- ence of proinflammatory cytokines. All tissue speci- though this study did not report any statistical analysis mens contained detectable amounts of IL-1a, IL-143, of the data, it did suggest a role for inflammatory TNF-a, and IL-6. Although the findings are clearly in- cytokines in the production of PGE,, an inflammatory triguing, limitations include the absence of quantified mediator known to induce pain and to enhance pain levels of cytokines and a lack of normal discs for com- sensitivity (Watkins and Maier 2000). parison. Furthermore, there was no attempt to measure Roberts and colleagues (2002) compared expres- pain perception using a reliable and valid pain sion of cytokines in herniated and nonherniated discs instrument. and found that all herniated samples had immunologi- ICang and others (1997) cultured normal and herni- cally detectable IL- IP, whereas fewer had detectable ated human intervertebral disc specimens to study the IL-6, MCP-I, thromboxane, or TNF-a. Nonherniated effects of IL-I43 on the production of nitric oxide, IL-6, discs had little or no detectable levels of these mole- prostaglandin E2 (PGE2), and MMPs. Herniated cervi- cules. Interestingly, when detected, these molecules cal and lumbar intervertebral disc specimens were col- were strongly associated with blood vessels. Statisti- lected from patients undergoing surgery for radicular cal analyses were not reported. symptoms. Normal intervertebral disc specimens (cer- Burke, Watson, McCormack, Dowling, and others vical and lumbar) were obtained from patients under- (2002) compared disc tissue from patients reporting going surgery for traumatic burst fracture or lumbar sciatica with that of patients who were undergoing sur- scoliosis surgery. These specimens served as the con- gery for discogenic low-back pain. Specimens from trol group. Tissue samples were then cultured in the patients undergoing lumbar discectomy were col- presence or absence of IL-Ip for 72 h. Normal, lected in which some had the annulus intact, some had nondegenerated disc specimens increased production nuclear extrusion, and some were sequestrated. Other of MMPs, nitric oxide, IL-6, and POE, in the presence specimens were collected from patients undergoing of IL-1p. Herniated disc samples had higher levels of lumbar interbody fusion for discogenic back pain, of nitric oxide, IL-6, and PGE, than did normal disc sam- which some had the annulus intact and some were ex- ples, but the production increased significantly in the trusion herniations. Significant quantities of IL-6, IL- presence of IL-1p. Although this study did not corre- 8, and PGE, were produced by tissue samples in both late pain indices with production of these molecules, it the sciatica and low-back pain groups. None of the did establish IL-1P as an inducer of degenerative and specimens produced TNF or IL- I. There was a signifi- EFTA00308040 202 BIOLOGICAL RESEARCH FOR NURSING Vol. 6. No. 1 January 2005 cant linear relationship between the production of IL-6 (Benoist 2002). In any case, the synergistic effects of and IL-8. Specimens of sequestrated disc from the sci- nerve compression and the altered chemical environ- atica group produced inflammatory mediators in ment of the IVD appear to produce the patho- quantities similar to the low-back pain group. A major physiologic network leading to the pain experienced weakness of this study was the absence of pain indices by those with herniated discs. and functional status among patients. This may have To identify the specific proinflammatory mediators provided insight regarding the relationship between involved, Onda and others (2002) studied the effects of pain, function, and cytokine levels. Furthermore, al- exogenous application of TNF-a on noci responses of though significant, correlations were low, suggesting dorsal horn neurons in the spinal cord at L, using anes- that other factors may be involved. thetized rats. Gelfoam containing 1 mma of rat recom- Specchia and others (2002) investigated the binant TNF-a or saline was applied to the nerve root cytokine profiles from herniated disc tissue among pa- trunk just cranial to the DRG for 2 h. The mean firing tients undergoing discectomy who reported symptoms rate in spontaneous discharges of neurons was re- of sciatica lasting longer than l year. Only protruded corded every 15 min. In the TNF-a-treated group, the intervertebral discs bulging into the spinal canal with- mean rate of spontaneous discharge of neurons began out breach of the posterior longitudinal ligament were to increase at 1 h after TNF-a application and lasted studied. Autopic L4.5 disc tissue from age-matched until the end of recording (120 min). In the DRG of the subjects with no history of back pain were used for TNF-a group, interstitial edema and enlarged capillar- control. Transforming growth factor-P1 (TGF-f31) ies were observed at 2 h postapplication. The control was expressed in herniated discs, particularly in group showed no apparent morphological changes. chondrocytes, endothelial cells, and in the granulation The results suggest that a small production of TNF-a tissue of the surrounding matrix. Insulin-like growth at the site of the nerve root may cause ectopic dis- factor-1 (IGF-1) was present in chondrocytes of both charges in the primary afferent fibers and thereby in- normal and pathological tissue, with a stronger label- duce prolonged excitation in the pain-processing neu- ing in the latter. IL-6 and IL-6R (IL-6R) rons responsible for radicular pain contributing to immunoreactivity was detected in the cytoplasm of hyperalgesia and spontaneous pain. chondrocytes of the protruded intervertebral discs. Aoki and others (2002) used pigs to study the ef- Herniated disc tissue exhibited significantly increased fects of epidural application of NP, IL-1P, TNF-a, levels for all cytokines compared with normal disc tis- interferon-y, or fat on NCV. Application of fat resulted sue. This study provided the first demonstration of the in a normal NCV 7 days later (74 ± 10 m/s) whereas expression of IL-6R in the chondrocytes of herniated the NCV in the NP group was significantly reduced tissue and confirmed the presence of TGF-f31, IGF- I, (40 ± 18 m/s). Both the IL-14i and INF-y displayed re- and IL-6, factors released in response to tissue duced NCVs (64 ± 27 m/s and 60 s-- 15 m/s), but the re- damage, in herniated disc tissue. ductions were not statistically significant. However, in the animals treated with TNF-a, a significant reduc- Alterations in the tion of the velocity was observed that was more pro- Biochemical Environment of the IVD nounced than that of the NP (32 ± 12 m/s). Although this study did not include pain indices, it does Together, these studies provide compelling evi- strengthen the possible role of TNF-a as the main me- dence of NP-induced effects on adjacent nerve root(s), diator responsible for reducing NCV in the nerve root. including nerve conduction velocity, mechanosensi- Ahn and colleagues (2002) investigated the correla- tization, pain behavior, histological degeneration, re- tion between the presence of cytokines and radicular duced blood flow, and increased endoneurial fluid symptoms in patients undergoing microdiscectomy. pressure. The biochemical changes initiated by ex- Radicular symptoms were assessed by motor, sensa- posed NP and the increased production of proinflam- tion, reflex, degree of pain onset in the straight-leg- matory cytokines create an environment of degrada- raising test, and development of radicular pain by back tion. This process has been hypothesized to be part of extension in 3 prone positions: full extension, elbow disc resorption, influenced by migrating macrophages support, and lying prone. All patients were asked to re- EFTA00308041  Starkweather and others / Neural-Immune Interactions 203 port their pain using a visual analog scale (VAS). The dromes. Much remains to be learned about the dynam- messenger ribonucleic acids (mRNAs) of IL-8, TNF- ics of immune system modulation of pain and neural a, IL-la, RANTES, and IL-10 were expressed in function. 70%, 65%, 39%, 17%, and 9% of the herniated disc Interestingly, to date, psychological measures and specimens, respectively. Furthermore, a significant as- the effect of stress on cytokine production have been sociation between IL-8 mRNA expression and the de- completely ignored. Yet one's psychological percep- velopment of radicular pain by back extension and tion has the potential to modulate biological mecha- radicular pain by elbow support on prone and lying po- nisms implicated in back pain and sciatica. A large sitions was observed. The mRNA expression of body of evidence demonstrates that perception of cytokines was not associated with the degree of pain stress and the resultant mood disturbance (depression onset in the straight-leg-raising test and pain scoring and anxiety) lead to enhanced proinflammatory according to the VAS. From this study, IL-8 appears to cytokine production. This has been demonstrated in be a pivotal chemokine involved in the evolution of numerous human paradigms and provides the linkage radicular pain. between the nervous and immune systems and cytokines (Biondi and Picardi 1999; Witek-Janusek Summary of Research Studies and Mathews 2000). Hence, the need to investigate possible correlations between biological mechanisms Replicating human disorders of the IVD in animals of pain (i.e., cytokines) and psychological factors that has proven difficult, as humans are the only obligate modulate the production of cytokines and the patient's bipedal vertebrate. However, animal models have pro- experience of pain are evident and need to be vided clues into the pathophysiologic effects of addressed in future studies. proinflammatory cytokines and have assisted in gener- ating new ideas for potential therapeutic treatment. In Conclusions and Clinical Implications addition, attaining satisfactory control in studies of random samples of human tissue has been equally The recognition that the immune system may be in- challenging. For instance, disc tissue procured during volved in neuropathic pain has important potential im- surgery is usually cut into portions, thereby making it plications. If proinflammatory cytokines contribute to almost impossible to determine the exact structure of pain and to neuropathological changes in the sensory the herniation actually involved in situ (protrusion vs. neurons, it may be possible to devise much-needed extrusion vs. sequestration) or the type of tissue pro- alternative approaches for treatment of patients with cured (nucleus pulposus vs. annulus fibrosis). In- low-back pain. Surgery for herniated discs is not cluded in this conundrum are the elements of lifestyle, without cost, and surgical treatment of disc body weight, and aging, all of which influence the load herniation is advised only if nonsurgical treatment environment of the normal IVD. Lifestyle and body fails. Furthermore, resolution of pain is not guaran- weight are capable of accelerating the rate of degener- teed with surgery, as complications and failure rates ation and thus further complicating the starting point remain relatively high (Cooper and Freemont 2004). from which to assess IVD degeneration. Understanding the role of the immune system in disc- The studies to date provide evidence of connective related pain may lead to a better appreciation of not tissue degradation, nerve and vessel ingrowth, and in- only the nature of organic pain but also alternative creased production of proinflammatory cytokines that therapeutic approaches or drug strategies to treat pain characterize IVD degeneration and herniation. There and its antecedents. Moreover, the evaluation of im- is considerable need for more investigation into the mune markers as indices of pain and of immune re- precise role of cytokines for each of these biological sponsiveness consequent to pain may provide insight processes. Concurrently, the study of immune involve- into the means by which to fine-tune the therapy pro- ment in neuropathic pain is in its infancy. Many more vided to individual patients. immune cells and immune-derived substances may be One such study involving diagnostic criteria sug- implicated in the etiology of pathological pain syn- gests that Modic changes may be an objective marker EFTA00308042 204 BIOLOGICAL RESEARCH FOR NURSING Vol. 6. No. 1 January 2005 of discogenic low-back pain. Modic changes are sig- TNF-ot receptors (etanercept) and selective antibodies nal intensity changes on plain radiograph x-rays and (infliximab) were used at therapeutic concentrations. magnetic resonance imaging that reflect a spectrum of The comparison group was treated with a heparin ana- vertebral body marrow changes associated with de- log (enoxaparin) to evaluate whether the prevention of generative disc disease. A correlation between Modic NP-induced nerve conduction velocity reduction was changes on spinal magnetic resonance images and the linked to a corresponding reduction of intraneural production of proinflammatory cytokines was ana- thrombus formation and edema. The control group had lyzed by Burke, Watson, McCormack, Fitzpatrick, saline applied. After 7 days, the NCV over the applica- and others (2002). They demonstrated a statistically tion zone was determined. The NCV was similar be- significant increase in the levels of IL-6, IL-8, and tween the saline and the enoxaparin groups at approxi- PGE2 in the disc tissue of patients with Modic changes. mately 50 m/s. In contrast, both the etanercept and the Modic 1 changes were more common in patients with infliximab groups displayed mean values of nerve discogenic low-back pain, whereas Modic 2 changes conduction velocities close to normal. Nerve fiber in- occurred in patients suffering from sciatica. jury was statistically less pronounced in the etanercept Traditional treatment for low-back pain includes and the infliximab groups compared with the nonsteroidal anti-inflammatory medication, which in- enoxaparin and saline groups, implying that nerve in- hibits prostaglandin synthesis, as first-line therapy. Pa- flammation induced by the NP was mediated by TNF- tients exhibiting sciatic symptoms are often prescribed a. The group treated with enoxaparin exhibited no steroids (by mouth or epidurally) to decrease swelling differences in NCV or histology compared to the in the affected nerve root. The use of these substances control group. in long-term therapy, however, must be weighed In a similarly designed study, Olmarker and others against their side effects. Gabapentin has been added (2003) evaluated the use of selective TNF-a inhibition to the armamentarium for treating neuropathic pain. on spontaneous behavior in the rat model of experi- Although its mechanism of action is unknown, it is mental disc herniation. After exposure, the L4.5 structurally related to the neurotransmitter y- intervertebral disc was incised and injected with a aminobutyric acid. All of these medications have lim- small amount of air. Sham exposure, in which the L" ited success in relieving symptoms of low-back pain vertebrae were visualized, served as a control. Some of and sciatica, and none prevent progression of the rats received an intraperitoneal injection of degenerative disease. 0.125 mL of 10 mg/mL infliximab, a known TNF-ot The recognition of peripheral and central immune inhibitor that exerts its effects through specific inacti- cell involvement in neuropathic pain of diverse etiolo- vating antibodies, before surgery. Behavioral analyses gies may offer a new avenue or approach to pain con- were performed the day before surgery and on days 1, trol. There are multiple situations in which immune- 3, 7, 14, and 21 after surgery. No difference in immobi- derived proteins (TNF, IL-1, IL-6) have been corre- lization behavior was observed in the rats for the first lated with and are the likely cause of neuropathic pain 14 days. At day 21, there was a statistically significant conditions (Watkins and Maier 2000). The pervasive higher immobilization in the rats in the nontreated NP and potentially key involvement of these series as compared to the sham. Locomotion was re- proinflammatory cytokines within an affected body duced in both groups exposed to NP at each time point, region or within the spinal cord are likely and desirable although the nontreated group showed a statistically targets for drug development. significant reduction as compared to the sham group. In a novel attempt to evaluate selective inhibition of Lifting of the leg on the operated side in the nontreated TNF-ot in NP-induced nerve injury, Olmarker and NP group was increased significantly compared to the Rydevik (2001) used autologous NP applied to the sham and treatment groups at days 1 and 3. Rotating porcine sacrococcygeal cauda equina. The pigs were the head toward the leg on the operated side was statis- subsequently given systemic treatment with selective tically significant in the nontreated NP group at days 3 TNF-ot inhibitors, etanercept, or infliximab. Soluble and 7 only, whereas this behavior was not observed in EFTA00308043  St