Nervous system diseases and pain: Pathophysiology and therapy (Proceedings)

Pain associated with intervertebral disk disease

Animals with acute intervertebral disk extrusion are almost always painful. The spinal cord itself does not possess pain receptors. Pain associated with intervertebral disk degeneration has been shown to be secondary to both biochemical mediators and nervous tissue impingement. The ligaments, joint capsule and bone of the spinal column are highly innervated The external periosteum, articular facet joint capsule and longitudinal ligaments receive sensory innervation by way of the medial branches of the dorsal rami of the spinal nerves. These rami form the recurrent sinuvertebral nerve. The dorsal longitudinal ligament and the ventral meningeal surface is highly innervated by complex encapsulated nerve endings and as well as poorly myelinated free nerve endings. These fibers also innervate the outer lamellae of the dorsal annulus fibrosus and direct stimulation of the intervertebral disk has been shown to induce pain. While the innervation to these structures are diverse and include postganglionic efferent fibers from the thoracolumbar autonomic ganglia (which mediate smooth muscle function of the vasculature of the spinal canal) and proprioceptive fibers (which modulate postural reactions), the majority of these fibers are nociceptive in function. In fact, it has been shown experimentally, that stimulation of tissues innervated by the sinuvertebral nerve elicits back pain. In the clinical setting, mechanical impingement of the nerve roots (radiculopathy) and meninges by extruded disk material and hypertrophy of supporting structures plays a role in generation of pain.

Disruption of the intervertebral disk and its ligaments and compression of nervous tissue leads to production of neuropeptides and other algesic molecules can activate nociceptors in the dorsal longitudinal ligament and dorsal annulus. The somata of the dorsal root ganglia make various algesic neuropeptides transported to central and peripheral terminals. Neurogenically-derived cytokines implicated include substance P and calcitonin gene-related protein (CRGP). Substance P has been shown be a part of the inflammatory cascade and generation of pain in radiculopathy. CGRP found in primary sensory neurons has been shown to mediate nociception and mechanoreception. Non-neurogenic-derived chemicals released during tissue damage (e.g. bradykinin, serotonin, histamine, and Pgs) also sensitize pain fibers. Extruded intervertebral disk material itself has been implicated as a source of biochemical mediators in the pathophysiology of radicular pain. In an in vitro study of human herniated disk material removed during decompressive surgery, nitric oxide, prostaglandin E2a, and interleukin 6 concentrations were elevated compared to nonherniated control disks from patients undergoing spinal surgery for other reasons (e.g. scoliosis correction). Nitric oxide is a novel mediator of inflammation and immune regulation. This biochemical has been shown to have both proinflammatory and anti-inflammatory functions. As a proinflammatory agent, it exerts strong vasodilatory effects promoting vascular leakiness resulting in edema. As an anti-inflammatory agent, it has been shown to inhibit production of IL-6, PgE2, and thromboxane. The exact function of nitric oxide in the disk and disk degeneration is not known at this time, however.

Pain associated with spinal cord compression/injury

Pain that originates from the spinal cord or nervous tissue (also referred to as central pain syndrome) is reported primarily in human patients following severe spinal cord injury. Following initial injury, the patient usually manifests acute pain which is the result of spinal column and adjacent soft tissue injury. Pain associated with spinal cord injury tends to occur months to years after the initial injury and is difficult to manage and treat. This type of pain should be considered a disease in and of itself, rather than a clinical manifestation of some other problem. The incidence is reported between 10-90% of all spinal cord injured patients and is often more of a concern to the patient than the residual functional disabilities. What is interesting is that this is not commonly recognized phenomenon in veterinary patients that are managed long-term following spinal cord injury but is reported in rodent models of spinal cord injury.

Pain associated from spinal cord injury may be spasticity related or may arise from the nervous system or both. The type of pain sensations reported is variable between patients. In people, pain of spinal cord injury can be divided into transitional zone pain and central dysesthesia syndrome. Transitional zone pain occurs at the level of the spinal cord injury and is often associated with nerve root injury. This type of pain seems to arise most commonly with thoracic level injuries. It is often present at a few contiguous spinal segments and is often asymmetrical. Transitional zone pains often "mimic" pain sensations that have been felt in the past. The pain occurs early as allodynia or hyperalgesia and may improve spontaneously. This type of pain is often addressed early in the course of the disease, therefore decreasing the chances of it becoming a long-standing illness. Severe, persistent cases are often treated with nerve blocks or dorsal root entry zone (DREZ) procedures.

Central dysesthesia syndrome is associated with a "burning" sensation below the level of the spinal cord injury. In contrast to transitional zone pain, is if often diffuse and symmetrical. The pathophysiology behind this syndrome has been studied but remains somewhat of an enigma. Multiple hypotheses have been generated, but it is not known if the same mechanisms underlie all central pain syndromes because there appears to be no one lesion type or location that is associated with a higher relative risk. This type of pain has been attributed to abnormal associations of the spinothalamic and dorsal column pathways that transmit pain information. The function spinothalamic tracts, which normally transmit protopathic sensations such as temperature and pain, are severely impaired. Patients with central pain often have abnormal pain and temperature sensibilities. Of interest is that lesions within the spinothalamic pathways are not required to induce this phenomenon, but rather tend to influence the character of the abnormal sensations. It appears that the critical disinhibition occurs in the ventroposterior, medial and intralaminar thalamic nuclei that receive and integrate information from the spinothalamic pathways. These thalamic regions in general tend to have an inhibitory influence on pain sensation. How these cells ultimately become disinhibited after spinal cord injury is not truly known; however, on a cellular level excitatory amino acids, glutaminergic N-methyl-D-aspartate (NMDA) and serotonergic receptors have been implicated. .

Central pain may remain stable, escalate in severity or decrease over time and can be very difficult to treat. Autonomic dysnergia, such as distend bladder or constipation, can result in increased pain transmission raising baseline pain levels in these patients.

Another complication of spinal cord injury is the development of syrinx within the parenchyma of the spinal cord (syringomyelia). This injury most commonly occurs years after the injury and is associated with ascension of the sensory and motor level dysfunction due to expansion as well as development of new pain sensations. Typically this pain is located to the region of the syrinx but may cause burning type pain above the level of the injury or syrinx. The natural course of syringomyelia is continued escalation of the pain that is often not responsive to pain medications or surgical intervention with syringopleural shunting. Post-injury or post-compression syrinx formation appears to be a more common source of pain in dogs than the enigmatic central pain syndromes.

Pain associated with nerve root compression

Pain is one of the key clinical features of lumbosacral stenosis and degenerative disease. While the causes of pain might seem some what obvious, the variable nature of the degree of pain and the lack of resolution of pain following decompressive surgery among individual human and animal patients remain an enigma. A tremendous amount of research has been conducted in both experimental and clinical settings to elucidate the underlying causes of low back pain and lumbosacral degenerative disease. Pain results from compression and inflammation of sensory nerve roots (radicular pain) and from degenerative and inflammatory changes in the articular facet joints, other supporting structures and the intervertebral disk (diskogenic pain). Local pathophysiology at the site of nerve injury has implicated a plethora of potential mediators of pain. All of these factors are not independent entities and are interrelated in a complex pathway.

On a basic nociceptive level, sensory innervation is present to all of the structures of the spine. Innervation to these structures primarily arises from the primary dorsal nerve root distal to the dorsal root ganglion. Recurrent articular nerves innervate the vertebral periosteum, articular facet joint capsules and ligamentous tissues of the dorsal neural arch (e.g. interarcuate ligament). Another branch forms the sinuvertebral nerve which enters back into the intervertebral foramen and gives rise to cranial and caudal branches that supply rich innervation to the dorsal longitudinal ligament and dorsal annulus fibrosus of the intervertebral disk. These two sensory nerves also have an intimate association with the autonomic plexus. Painful or pathologic conditions of these nerves or structures innervated by them may result in autonomic manifestations. Less attention has been given to pain generated from compression and inflammation of the dura mater. Sensory innervation of the dura mater is provided by the sinuvertebral nerve which carries both sensory and sympathetic fibers. A large number of peptidergic (pain-associated) nerve fibers are distributed throughout the dura mater and likely play a role in generation of pain.

The nerves of the cauda equina, in the normal state, are somewhat moveable in the spinal canal and intervertebral foramen to accommodate changes in spinal extension and flexion and movement of the pelvic limbs. When the nerve roots become compressed or entrapped by extruded intervertebral disk, hypertrophied tissues or canal stenosis, the movement of the nerve root becomes limited and traction and compression of the nerve root induces pain mechanisms and morphologic changes in the nerve. Chronic compression can be thought of as repeated episodes or persistence of acute compression. Direct mechanical and chemical or mechanical injury alone to lumbar roots in the rat produces mechanical allodynia and thermal hyperalgesia. Pain, allodynia and numbness are subjective symptoms of lumbar radiculopathy that may be induced by ectopic or spontaneous firing of nociceptive sensory neurons. Excitability and spontaneous firing in the dorsal root ganglion has been shown to be linked to sensory nerve sodium-gated channels recently implicated in neuropathic pain. Mechanical compression has additionally been shown to lead to intraneurial tissue reaction, including edema formation, demyelination and fibrosis. Various morphologic and physiologic changes occur with separate phases (acute, subacute and chronic) of nerve root compression. A chemically-induced inflammation of the nerve root by presence of ruptured disk tissue disseminated along the root sheath has been proposed as another mechanism of pain.

Decreased blood flow within nerve roots or the cauda equina may play a role in the symptoms seen in patients with degenerative or stenotic lumbosacral disease. Blood flow is shown to be negatively affected by experimental nerve root constriction and hypoxic stress was shown to induce ectopic firing in the dorsal root ganglion and increased sensitivity to mechanical stimuli. A large number of sensory roots pass through the dorsal root ganglion which has an abundant vascular network and no blood-nerve barrier. Compression likely occurs first in thin-walled venules which results in impaired perfusion of the capillary system that feeds the nerve roots producing ischemia and augmenting radicular edema. Increased vascular permeability and subsequent edema in the remainder of the root are attributable to a break down in the blood-nerve barrier. Endoneurial edema, which experimentally has been temporally shown to be associated with the onset of nerve root pain and neurological dysfunction, is observed in the dorsal root ganglion during compression. Edema results in high pressures exerted on the ganglion cells because the perineurium prevents leakage into the epineurium and the fluid is retained. The edema may then increase the functional compression in addition to the mechanical stress and contribute to the impaired cell functions.

The nervous system is considered immunologically privileged, meaning that it is not typically surveyed by circulating lymphocytes like other organs. Nerve root injury may produce a cascade of events that upregulates cell adhesion molecules which enable entry of the hematogenous cells into the CNS contributing to neuroinflammation and the development of central sensitization. The upregulation of these molecules has been temporally associated with the onset of mechanical allodynia after nerve root injury. Additionally, these changes were associated with the dorsal horn laminae in which nociceptive sensory fibers terminate. Increased expression cell adhesion molecules and membrane glycoproteins have been demonstrated with various disease processes of the CNS and PNS including infection, autoimmune inflammation and nerve root compression.

Experimental models have produced evidence for central neuroinflammation from nerve root compression which includes astrocyte and glial activation and increased expression of proinflammatory cytokines Local production of proinflammatory cytokines via immune cell activation has been implicated in enhanced nociceptor activity. The CNS becomes infiltrated by immune cells from the peripheral circulation. Microglia and astroctyes also become activated in response to peripheral nerve or nerve root injury and release pro- and anti-inflammatory molecules, chemokines, and cellular adhesion molecules.

T cells recognize myelin sheath breakdown products and release macrophage activating factors such as γ-interferon. Activated macrophages begin to infiltrate locally to remove cellular debris and release inflammatory cytokines like IL1-β, nitric oxide and TNF-α. TNF-α has been shown to produce hypersensitivity when applied epineurially which was blocked when antibodies against TNF-α were co-administered. TNF-α and nitric oxide may potentiate further demyelination by Schwann cell injury, and nitric oxide also contributes to increased vascular permeability and pain. Prostaglandins, which also play an important role in inflammation, have not been shown to have a direct nociceptive effect but may lower the pain threshold at sensory nerve endings. In addition, algesic spinal neuropeptide expression (Calcitonin Gene-Related Peptide, or CGRP and substance P, or SP) was shown in models of nerve root compression.

The amino acid glutamate is one of the most ubiquitous neurotransmitters and has been shown to be associated with pain processing throughout the nervous system. Glutamate antagonists that work at NMDA, AMPA and kainite receptors have been shown to attenuate pain responses in rat models. While the actions of glutamate in the dorsal root ganglion are not completely known, the cell bodies have been shown to possess a high density of glutamate receptors colocalized with nociceptive neurons and mechanisms for reuptake of glutamate from the neuromuscular junction have be identified. Glutamate is also found to be abundant in the extracellular matrix of the intervertebral disk with concentrations significantly higher in the herniated disk material suggesting release of glutamate from the proteoglycan structure. Results from one study suggested that there dorsal root ganglion cells were capable of glutamate uptake from the epidural space and that there was relatively low concentration of glutamate normally present in the epidural space resulting in a steep concentration gradient diffusing from the herniated intervertebral disk material into the dorsal root ganglion.

Pain from lumbosacral disease is characteristically chronic in its nature. Nerve injury may lead to potentiation of central sensitization and the development of chronic lumbar radiculopathy. It has been shown that long-term potentiation occurs in the spinal cord in response to noxious stimulation or injury to peripheral nerves. Moreover, early on, pronounced spinal neuroimmune activation and inflammation induces central sensitization by directly or indirectly inhibiting interneuron inhibitory activity at the dorsal horn in the spinal cord. Glial and neuronal proinflammatory cytokines can sensitize the peripheral nociceptive fields and dorsal root ganglia. Glial cells synthesize proinflammatory cytokines, proteases, inducible-NO, excess glutamate, oxygen free radicals, eicosanoids and other toxins that act at the NMDA (N-Methyl-D-Aspartate) receptors that are implicated in central nervous system sensitization.