Nerve root compression in association with disc herniation can result from acute insult to the axonal, connective, and vascular tissues of the nerve root and initiate a cascade of related and integrated neuronal, inflammatory, and degenerative changes (Kobayashi et al. 2004b; Rydevik et al. 1984, 1994; Winkelstein et al. 2002). From this perspective, mechanical injury and inflammatory injury are not unique, nor unlinked, events. Nerve root compression following acute mechanical loading can induce long-term nerve root pathophysiology, such as edema, inflammation, and thickening of connective tissues (Beck et al. 2010; Jancalek and Dubovy 2007; Kobayashi et al. 2004b; Mosconi and Kruger 1996), as well as the development of evoked pain via modified communication with the spinal cord. Following mechanical trauma and compression, injured axons exhibit axonal swelling, loss of cytoskeleton proteins, separation and disorganization of the myelin sheath, loss of axonal transport, Wallerian degeneration, and a decrease in axon packing density (Guertin et al. 2005; Jancalek and Dubovy 2007; Kobayashi et al. 2004a, b, 2005a, b, c, d; Mosconi and Kruger 1996; Myers et al. 1993). Like functional changes in neurons during and after compression, degenerative changes in axons develop at later times and are also dependent on the magnitude of the compression (Hubbard et al. 2008b; Kobayashi et al. 2005b; Nicholson et al. 2011).

Cells that respond to injury include microglia (resident macrophages in the central nervous system) and astrocytes. These cells have many roles in both the peripheral and ­central nervous systems, including the maintenance of homeostasis at neuronal synapses. Both types of glial cells respond to injury by changing their morphology, proliferating, upregulating cell surface markers, and releasing several inflammatory mediators (Cao and Zhang 2008; DeLeo et al. 2004; Saab et al. 2008; Suter et al. 2007). A peripheral stimulus by some neurotransmitters/neuromodulators (e.g., excitatory amino acids, substance P, ATP) (Cao and Zhang 2008; Marriott 2004) can activate early release of proinflammatory cytokines as well as nitric oxide, prostaglandins, and nerve growth factor (DeLeo et al. 2004; Inoue 2006). These mediators, in turn, induce an exaggerated release of neurotransmitters from presynaptic neurons, sensitize the postsynaptic membrane, activate neighboring astrocytes, and enhance microglial activity (DeLeo et al. 2004; Inoue 2006). This positive feedback sustains the release of pain mediators, facilitating the development of neuronal hypersensitivity and can lead to the persistent pain that is often associated with a herniated disc or inflamed nerve root. Following such neural insults, spinal glial cells become activated and modulate other ­immunologic changes via cytokine and growth factor production, leading to persistent pain (DeLeo and Yezierski 2001; Hashizume et al. 2000a; Obata et al. 2004; Winkelstein et al. 2001a). In particular, greater nerve root compression leads to increased activation of spinal astrocytes that is apparent as early as 1 day and is sustained in parallel with persistent symptoms of mechanical allodynia (Rothman and Winkelstein 2007). These observations suggest that spinal astrocytes may directly respond to the changes in the dorsal horn that are induced by damaged primary afferents (Hogan 2007; Sapunar et al. 2005) (Fig. 19.4).

Severe axonal injury can also induce Wallerian degeneration of the axonal process distal to the cell body (Stoll and Jander 1999; Stoll and Muller 1999). For the central axons of primary afferents, which make up the dorsal nerve root, Wallerian degeneration can occur proximal to the site of injury (Hubbard and Winkelstein 2008; Kobayashi et al. 2008). Axonal degeneration, marked by neurofilament degradation and loss of axonal integrity, is evident as early as 15 min after trauma, but is more commonly present at time points in the order of weeks (Kobayashi et al. 2008; Ramer et al. 2004). The extent of degeneration is modulated by the mechanics of the insult and is associated with persistent pain and hypersensitivity after a compression to the nerve root (Dyck et al. 1990; Hubbard et al. 2008a, b; Kobayashi et al. 2008; Nicholson et al. 2011) (Fig. 19.5). Disruption to the axonal structure has been found to be more pronounced for greater loads applied for longer durations (Dyck et al. 1990; Hubbard et al. 2008a; Kobayashi et al. 2005a, 2008; Nicholson et al. 2011). Further, the extent of damage and Wallerian degeneration of the axons in the compressed nerve root is directly related to the development of persistent hypersensitivity (Hubbard et al. 2008a, b; Hubbard and Winkelstein 2008).

The severity of nerve root injury and the intensity of pain after nerve root injury inflammation strongly relate to neuropeptide depletion in the DRG and spinal cord together with axonal degeneration (Hubbard et al. 2008a, b; Rothman et al. 2005). For example, persistent allodynia, due to higher magnitudes of dorsal nerve root compression, is associated with greater sensitivity at 1 week or later (Hubbard et al. 2008a, b). This is accompanied by a corresponding depletion of the nociceptive neuropeptide, substance P, in the DRG that similarly varies with the magnitude of the initiating compressive load (Hubbard et al. 2008b; Kobayashi et al. 2005b). Spinal expression of another potent neuropeptide for regulating pain, calcitonin gene-related peptide (CGRP), also decreases with increased painful loading to the nerve root (Hubbard et al. 2008a, b). Together with the effects of neural trauma described above, these mechanically deleterious events can dramatically contribute to reduced transport of ­neuropeptides and neurotrophic factors from neurons, where these factors are synthesized, to their release from the presynaptic terminals in the spinal cord.

In animal models, the magnitude, duration, and rate of the nerve root compression have been shown to modulate the extent of the local tissue damage to the root and the degree and duration of the pain-related behaviors (Kobayashi et al. 2005a; Olmarker et al. 1989; Rothman et al. 2010; Rydevik et al. 1991; Winkelstein et al. 2002). In rodent models of nerve root compression, elevated magnitudes of compression increased the levels of mechanical allodynia and reduced axonal transport in the compressed root (Kobayashi et al. 2005a; Winkelstein et al. 2002). Although animal models of nerve root compression have shown sustained mechanical hypersensitivity in the affected limb (Colburn et al. 1999; Hashizume et al. 2000a; Kobayashi et al. 2005a; Winkelstein and DeLeo 2004; Winkelstein et al. 2002), mechanical hypersensitivity can also be produced when the nerve root is compressed for times as short as 2 s (Sekiguchi et al. 2003, 2009). Moreover, lumbar nerve root compression produces an immediate change in evoked signal conduction along the fibers of the compressed root (Fumihiko et al. 1996; Morishita et al. 2006; Pedowitz et al. 1992; Rydevik et al. 1991; Takahashi et al. 2003). Both compression rate and magnitude contribute to edema production in the nerve root, such that the magnitude of pressure required to produce edema decreases for higher loading rates (Hubbard et al. 2008b; Hubbard and Winkelstein 2008; Nicholson et al. 2011, 2012; Olmarker et al. 1989; Rothman et al. 2010; Rydevik et al. 1991). Moreover, specific loading parameters, such as ­magnitude and duration, likely play a role in modulating electrophysiologic responses. Animal models of nerve root compression in the cauda equina demonstrate that evoked neuronal signaling is altered during and after compression (Fumihiko et al. 1996; Garfin et al. 1990; Pedowitz et al. 1992; Rydevik et al. 1991) and decreases in the amplitude of electrically evoked compound nerve action potentials due to cauda equina compression may persist after removal of the compressive force (Pedowitz et al. 1992; Rydevik et al. 1991). These changes are corroborated by measurements in human subjects with intervertebral disc herniation that similarly show changes in evoked nerve action potentials upon straight-leg raise.

The results of studies of mechanically compressed nerve roots together with the widespread molecular changes can be integrated into a generalized schema. As early as 1 h following even a transient nerve root compression that is sufficient to produce persistent behavioral sensitivity, inflammatory cytokines, IL-6 and TNF-α, and mRNA expression levels are ­elevated in the ipsilateral DRG and also in the spinal cord (Rothman et al. 2009b). Within 1 day of that event, behavioral sensitivity develops along with hallmarks of spinal inflammation, including activation and proliferation of microglia (Rothman et al. 2009a). By 7 days after injury, axons of the injured nerve root show signs of degeneration, and the spinal inflammation becomes even more pronounced, and both astrocytes and microglia become activated (Hubbard and Winkelstein 2005, 2008). These changes together with the decrease in neuropeptides in the spinal cord at this same time point (Hubbard et al. 2008b) may lead to alterations in neuronal signaling in the spinal cord following a painful injury.

As mentioned above, contributing to a cascade of chemical injuries at the affected nerve are elevated levels of inflammatory mediators, infiltration of macrophages, and activation of glial cells. To further examine these effects, animal models have been developed that mimic features of both inflammation and immune system function in intervertebral disc herniation. Both behavioral hypersensitivity and widespread immune responses are produced when chromic gut suture pieces are placed in contact with the nerve root without any mechanical perturbation (Colburn et al. 1999; Hashizume et al. 2000a; Hou et al. 2003; Hubbard and Winkelstein 2005; Kajander et al. 1996; Kawakami et al. 1994a, b; Maves et al. 1993; Murata et al. 2004a, b; Olmarker et al. 1993; Rothman and Winkelstein 2007; Rutkowski et al. 2002; Winkelstein and DeLeo 2004). Gut suture ligation simultaneously compresses the nerve root by ligation, while the chromic salts and pyrogallol in the suture serve as irritants (Colburn et al. 1999; Hashizume et al. 2000a; Kajander et al. 1996; Kawakami et al. 1994a, b; Maves et al. 1993; Robinson and Meert 2005; Winkelstein and DeLeo 2004; Xu et al. 1996). A consistent response to the chromic gut suture by the nerve root damage is the induction of thermal hyperalgesia (decreased latency to withdraw from thermal stimuli) that is transient and dose dependent; this form of hyperalgesia is not consistently present in intervertebral disc herniation models that mimic the compressive stimuli alone (Maves et al. 1993; Yamamoto and Nozaki-Taguchi 1995). The mechanisms governing the neuronal responses to chromic gut salts appear to be related to early immune activation characterized by Schwann cell proliferation, macrophage infiltration, and microglial activation. Along with these changes are molecular events including a depleted neuropeptide expression and an early expression of cell adhesion molecules such as ICAM-1 and PECAM. These adhesion molecules would serve to promote recruitment of circulating monocytes to the injured nerve root (Chang and Winkelstein 2011; Hashizume et al. 2000a; Rothman et al. 2010; Rutkowski et al. 2002; Xu et al. 1996; Yamamoto and Nozaki-Taguchi 1995). These studies indicate that, despite similarities in sensitivity to chromic gut suture and mechanical compression, differences in the pattern of hypersensitivity and molecular changes may reflect only limited injury etiologies. Nonetheless, use of chromic gut sutures as a chemical injury model for nerve root damage is popular for evaluating treatments that can interfere in the perception of disc herniation-related pain.

Soft tissues of the disc are believed to be immune privileged, in that the internal structures of the intervertebral disc do not come into contact with the systemic circulation under normal conditions and express the Fas ligand that can ­promote an autoimmune response. With degeneration and damage, the internal structures of the intervertebral disc can come in contact with adjacent tissues, producing an immune response that is the subject of extensive investigation. Intervertebral disc tissues contain high levels of CD68+ immunoreactive macrophages, as well as lesser quantities of T and B lymphocytes (Doita et al. 1996; Freemont et al. 2002; Gronblad et al. 1994; Roberts et al. 2006; Shamji et al. 2010). In addition, the disc tissues secrete numerous proinflammatory cytokines and inflammatory mediators, such as interleukin-1α (IL-1α), interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α); these cytokines may be produced by primary disc cells or by infiltrating monocytes (Bachmeier et al. 2009; Burke et al. 2002; Le Maitre et al. 2007; Murata et al. 2004a; Saal 1995; Shamji et al. 2010; Weiler et al. 2005, 2011) (Table 19.1). Numerous studies have documented the molecular effects of the herniated discal tissues (Mulleman et al. 2006a, b). Models used for these studies have included harvest of tail nucleus pulposus tissue for placement at a lumbar nerve root or cauda equina (Allen et al. 2011; Aoki et al. 2002; Brisby et al. 2000; Cuellar et al. 2005; Kawakami et al. 1999; Shamji et al. 2009; Skouen et al. 1999; Yabuki et al. 1998) or lumbar disc puncture to promote nucleus pulposus herniation (Olmarker et al. 1998; Olmarker and Myers 1998; Otani et al. 1997). Physiological changes noted in these models include reduced nerve conduction velocities, lowered endoneurial pressure for dorsal horn or sensory neurons, and elevated nitric oxide synthase activity in spinal nerve roots at 1–4 weeks following exposure to discal tissues. In addition, there is increased expression of neurotrophins, IL-1β, TNF-α, phospholipase-1, and/or nitric oxide synthase in the applied nucleus pulposus tissues or in cell bodies and intercellular domains around the DRG (Kallakuri et al. 2005; Kawakami et al. 1999; Murata et al. 2004a; Onda et al. 2002). Disc-associated cytokines (IL-1β, TNF-α, IFN-γ) applied directly to nerve roots, as opposed to cytokines secreted by nucleus fragments, have also been shown to induce electrophysiological changes, consistent with a heightened sensitivity (Ozaktay et al. 2002; 2006). It is likely that these cytokines bind to receptors for TNF-α and IL-1β on the sensory neurons (Binshtok et al. 2008; Verri et al. 2006). While these findings clearly indicate a role for inflammation and inflammatory mediators in regulating neuronal sensitivity in intervertebral disc herniation, it must be noted that many changes in the nucleus pulposus-induced or chemical injury models of radiculopathy overlap with those reported for direct compression neuropathy.

As with direct nerve root compression or chromic gut suture exposure, application of nucleus pulposus tissue to a naïve nerve root induces limb hypersensitivity that is largely characterized by a mechanical allodynia (Hou et al. 2003; Mulleman et al. 2006a, b) (Fig. 19.5). Many studies of nucleus pulposus-induced radiculopathy following disc puncture to induce nucleus herniation or placement of nucleus pulposus tissue upon the nerve root report evidence of allodynia as early as 2 days that may persist out to 3 weeks (Kawakami et al. 1999; Obata et al. 2002). Early studies also report functional changes following nucleus pulposus-induced radiculopathy, including altered footprints and visual evidence of limping, paw lift, or rotation of the head (Olmarker et al. 1998, 2002). With the use of quantitative gait analysis, our laboratories have further demonstrated gait asymmetries between ipsi- and contralateral hind limbs out to 3 or 4 weeks postoperatively, indicative of limping (Shamji et al. 2009) (Fig 19.3). Static and dynamic gait analyses indicate that animals with radiculopathy bear less weight on their affected hindpaw in both stance and during locomotion (Allen et al. 2012).

The findings discussed above suggest that radiculopathy induced by DRG exposure to nucleus pulposus tissue, as a model of intervertebral disc herniation, can repeatedly mimic key characteristics of prolonged pain sensitivity in the human patient (Allen et al. 2011; Shamji et al. 2009). The finding of persistence of sensitivity supports the notion that the molecular responses of an inflamed disc may influence sensory changes during intervertebral disc herniation. The persistent sensitivity changes, extending beyond fragment removal or resorption, imply that the widespread responses imitated in the CNS and even systemically are not ameliorated. Once initiated, the neuroimmune cascade involves activation of many nonneuronal cells in the peripheral tissues (DeLeo and Yezierski 2001; Julius and Basbaum 2001; Moalem and Tracey 2006). These resident cells, including mast and Schwann cells, release mediators such as histamine, prostaglandins, cytokines, and chemokines that also lead to the recruitment of other infiltrating immune cells (e.g., neutrophils, macrophages, lymphocytes) (DeLeo and Yezierski 2001; Moalem and Tracey 2006; Verri et al. 2006). Proinflammatory cytokines also trigger the release of many other inflammatory mediators that can sensitize nociceptors, further maintaining neuronal excitability and sensitization and leading to dysfunction and pain (Moalem and Tracey 2006; Verri et al. 2006). Nonetheless, the persistence of pain observed in some human subjects following intervertebral disc herniation that may continue for months and even years has not been replicated in these animal models, where mechanical allodynia or thermal hyperalgesia can recover to control or preoperative values at later times after surgery. Additional studies of CNS sensitization in human and animal models of disc herniation are needed to better understand the role of these important pathway changes in the pathogenesis of disc pain.

Taken together, with knowledge gained from direct nerve root compression studies, it becomes clear that many of the sensitization and functional changes associated with disc herniation may reflect contributions from both compressive trauma as well as inflammatory agents in the disc. While somewhat intuitive, the more severe nerve root injuries (with greater degrees of tissue impingement) produce more pain-associated behavioral sensitivity than those injuries with less tissue compression (Hubbard et al. 2008b; Hubbard and Winkelstein 2005; Winkelstein et al. 2001b, 2002). This graded relationship has been shown to hold true regardless of the absence or presence of molecular challenges (Winkelstein and DeLeo 2004). Indeed, evidence that the duration of the mechanical trauma modulates several different pain pathways strongly supports the concept that a more permanent mechanical insult would produce a similar or even more robust deleterious clinical effect. Based on these understandings, clinical interventions, and specifically nonsurgical therapies, are focused on alleviating the persistent sensitivity that is associated with a transient or more chronic compressive trauma to the nerve root and the associated inflammatory events. This topic is briefly covered in the next section on emerging pharmacological approaches to treat intervertebral disc herniation-associated radiculopathy.