Current Understanding of Spinal Pain and the Nomenclature of Lumbar Disc Pathology

Chapter 2 Current Understanding of Spinal Pain and the Nomenclature of Lumbar Disc Pathology



Kyung-Hoon Kim, MD, PhD, Inn-Se Kim, MD, PhD


Any structure to be deemed a cause of back pain should:


▪ Have a nerve supply.

▪ Be capable of causing pain similar to that seen clinically, with this capability ideally demonstrated in normal volunteers.

▪ Be susceptible to diseases or injuries that are known to be painful.

▪ Have been shown to be a source of pain in patients through the use of diagnostic techniques of known reliability and validity.

Tissues capable of transmitting pain in the back are as follows:


▪ Common sources of spinal pain that can be confirmed as such by radiography, computed tomography (CT), magnetic resonance imaging (MRI), or electromyography (EMG)/nerve conduction velocity (NCV) testing include intervertebral discs, facet joints, spinal cord or nerve root dura, sacroiliac joints, and atlantoaxial and atlantooccipital joints.

▪ Common sources of spinal pain that are identified through medical history or a physical examination include vertebrae, muscles, fascia, and ligaments.


General pain mechanism


The two categories of pain are as follows:


▪ Spontaneous pain may be continuous or intermittent, superficial or deep, and may elicit different subjective sensations described as burning, shock-like, aching, and so on.

▪ Stimulus-evoked pain occurs in response to mechanical, thermal (cold and heat), or chemical, low- or high-intensity stimuli applied statically or dynamically to skin, joints, bone, muscle, or viscera.

Potential associations between particular mechanisms and particular symptoms are as follows:


▪ A reduced pain threshold to heat stimuli applied directly to a site of inflammation can be associated with peripheral sensitization.

▪ Tactile allodynia in a noninflamed area can be associated with an N-methyl-D-aspartate (NMDA) receptor–mediated central sensitization.

▪ Spontaneous burning pain can be associated with activity of C fibers.

▪ Paresthesia can be associated with activity of ectopic A fibers.

The pain evoked by different input channels represents operation of multiple mechanisms, such as the following:


Nociceptive transduction: Activation of high-threshold receptor–ion channel transducers in nociceptor peripheral terminals

Peripheral sensitization: Change in threshold sensitivity of receptor–ion channel transducers in nociceptor peripheral terminals

Altered sensory neuron excitability: Changes of the expression-phosphorylation-accumulation of ion channels in primary afferents

Central sensitization: Post-translational changes in ligand- and voltage-gated ion channel kinetics in central (spinal cord and brain) neurons, which change the neurons’ excitability and the strength of their synaptic inputs

Phenotype modulation: Alterations in the expression of receptors, transmitters, and/or ion channels in peripheral and central neurons

Synaptic reorganization: Modification of synaptic connections caused by cell death or sprouting

Disinhibition: Loss of local inhibition at different relay levels in the neuraxis and of descending inhibition originating in the forebrain and brainstem and terminating in the brain stem and spinal cord, caused by decreased activation of neurons, downregulation of receptors-transmitters, and cell death

A number of different input channels can lead to the pain sensation. These should be the first anatomic targets for treatment (Fig. 2-1; Table 2.1), as follows:


▪ Nociceptive pain: Nociceptor activation in the periphery by noxious mechanical-thermal or chemical stimuli.

▪ Peripheral sensitization: Activation of sensitized nociceptors in the periphery by low-intensity stimuli.

▪ Peripheral nerve injury: Ectopic discharge in nociceptors originating at a neuroma, a dorsal root ganglion, a peripheral nerve, or a dorsal root.

▪ In combination with central sensitization, synaptic reorganization, or disinhibition: Low-intensity afferent activation in the periphery by low-intensity mechanical-thermal stimuli.

▪ Peripheral nerve injury associated with central sensitization, synaptic reorganization, or disinhibition: Ectopic discharge in low-threshold afferents originating at a neuroma, dorsal root ganglion, peripheral nerve and/or dorsal root.

▪ In the dorsal horn, thalamus, or cortex: Spontaneous activity in central neurons.

image

Figure 2–1 A diagrammatic representation of the relationships among the disease or injury, mechanisms, symptoms, and pain syndromes. The ideal for pain management is to treat the mechanisms apart from disease-modifying therapy.


(Adapted from Woolf CJ, Max MB: Mechanism-based pain diagnosis: Issues for analgesic drug development.Anesthesiology 2001;95:241-249.)



Table 2.1 Drug Treatment Based on Pain Mechanism Molecular Targets*

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The four primary types of pain (Fig. 2-2) are as follows:


Nociceptive pain: transient pain in response to a noxious stimulus

Inflammatory pain: spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation

Neuropathic pain: spontaneous and hypersensitivity to pain in association with damage to or a lesion of the nervous system (the symptoms of neuropathic pain are described in Box 2.1)

Functional pain: hypersensitivity to pain resulting from abnormal central processing of a normal input

image

Figure 2–2 The four primary types of pain. A. Nociceptive pain: transient pain in response to a noxious stimulus, B. Inflammatory pain: spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation, C. Neuropathic pain: spontaneous and hypersensitivity to pain in association with damage to or a lesion of the nervous system, D. Functional pain: hypersensitivity to pain resulting from abnormal central processing of a normal input.


(From Woolf CJ: Pain: Moving from symptom control toward mechanism- specific pharmacologic management.Ann Intern Med 2004;140:441-451.)



BOX 2.1 Positive and Negative Symptoms of Peripheral Neuropathic Pain


Woolf CJ: Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 2004;74:2605-2610.



Positive Symptoms



Spontaneous pain

Paresthesia

Dysesthesia

Allodynia

Hyperalgesia/hyperpathia


Negative Symptom



Loss of sensation

Adaptive pain and maladaptive pain are defined in Box 2.2.



BOX 2.2 Two Broad Classes of Pain


Modified from Woolf CJ; American College of Physicians; American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441-451.



Adaptive Pain


“The good”


Pain that contributes to survival by protecting the organism from injury or promoting healing when injury has occurred (nociceptive pain)


Coupled from a noxious stimulus or healing tissue



Maladaptive Pain


“The bad and the ugly”


An expression of the pathologic operation of the nervous system (neuropathic pain) or abnormal operation of the nervous system (functional pain)


Uncoupled from a noxious stimulus or healing tissue


Pain as disease


Multiple mechanisms that can produce pain, as follows:


Nociception: The sole mechanism that causes nociceptive pain and is comprised of the processes of transduction, conduction, transmission, and perception.

Transduction: The conversion of a noxious thermal, mechanical, or chemical stimulus into electrical activity in the peripheral terminals of nociceptor sensory fibers. This process is mediated by specific receptor ion channels expressed only by nociceptors (Fig. 2-3).

Conduction: The passage of action potentials from the peripheral terminal along axons to the central terminal of nociceptors in the central nervous system.

Transmission: the synaptic transfer and modulation of input from one neuron to another (Fig. 2-4).

Central sensitization: Contributes to inflammatory, neuropathic, and functional pain (Figs. 2-3 and 2-5).

image

Figure 2–3 A, The peripheral terminal of a nociceptor sensory neuron. The different transducing receptor and ion channels that respond to thermal, mechanical, and chemical stimuli are shown. MDEG, mammalian degenerin; P2X, purinergic receptor; TRM3, 2’-O-ribose methyltransferase 3. B, The mechanism of peripheral sensitization. Inflammatory mediators, such as prostaglandin E2 (PGE2), bradykinin (BK), and nerve growth factor (NGF), activate intracellular kinases in the peripheral terminal that phosphorylate transducer channels to reduce their threshold or sodium channels to increase excitability. C, Transcriptional changes in the dorsal root ganglion (DRG). Activity, growth factors, and inflammatory mediators act on sensory neurons to activate intracellular transduction cascades. These cascades control the transcription factors that modulate gene expression, leading to changes in the levels of receptors, ion channels, and other functional proteins. AA, arachidonic acid; ASIC, acid-sensing ion channel; ATP, adenosine triphosphate; CaMKIV, calcium/calmodulin-dependent protein kinase IV; Cox2, cyclooxygenase-2; ERK, extracellular signal-regulated kinase; EP, prostaglandin E receptor; JNK, jun kinase; mRNA, messenger RNA; Nav1.8/1.9, voltage gated sodium channel type 1.8/1.9; NGF, nerve growth factor; P38, serinethreonine kinase; PKA, protein kinase A; PKC, protein kinase C; TRP, transient receptor potential.


(From Woolf CJ: Pain: Moving from symptom control toward mechanism-specific pharmacologic management.Ann Intern Med 2004;140:441-451.)


image

Figure 2–4 Contributions of spinal cord dorsal horn neurons to pain. A. Nociceptive transmission. B. The acute phase of central sensitization. C. The late phase of central sensitization. Some alterations in gene expression are activity-driven and restricted, such as dynorphin, whereas others are widespread and produce diverse changes in function, such as induction of cyclooxygenase-2 (COX-2) in central neurons after peripheral inflammation. D. Disinhibition. AA, arachidonic acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; EP, prostaglandin E receptor; IL-1, interleukin-1; NK1, neurokinin 1; NMDA, N-methyl-D-aspartic acid; PGE2, prostaglandin E2.


(From Woolf CJ: Pain: Moving from symptom control toward mechanism-specific pharmacologic management.Ann Intern Med 2004;140:441-451.)


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Figure 2–5 Scheme of the Major Signaling Pathways that Regulate TRP Ion Channels. (+) represents sensitization or activation; (−) represents desensitization. In the early phase of inflammation, increased pain sensitivity originates largely as a result of the local release from inflammatory cells of a number of mediators. Most of these inflammatory mediators do not directly activate nociceptors, but rather act as sensitizers, reducing the threshold of the peripheral nociceptor terminals. Among the major inflammatory mediators are prostanoids, particularly prostaglandin E2 (PGE2), bradykinin, and nerve growth factor. These chemicals acting through EP prostaglandin and B1/B2 bradykinin G protein-coupled receptors and the high-affinity TrkA NGF receptor produce their immediate effects on pain hypersensitivity locally on the nociceptor terminals by phosphorylating TRPV1 as well as the sensory neuron-specific voltage-gated sodium channel Nav 1.8. Activation of the protease-activated receptor 2 by inflammatory proteases like trypsin has a similar effect. Phosphorylation and dephosphorylation substantially alter TRPV1 ion channel function, and this represents a major means of rapidly and dynamically altering pain sensitivity. AA, arachidonic acid; AC, adenylate cyclase; AKAP, A-kinase anchor proteins; B2R, bradykinin receptor 2 (BDKRB2); CaM, calmodulin; CaMKII, calmodulin dependent kinase II; COX, cyclooxygenase; DAG, diacylglycerol; EET, epoxyeicosatrienoic acids; EP, prostaglandin E; ER, endoplasmic reticulum; ERK, extracellular-signal-regulated kinases; G11, guanine nucleotide-binding (G) protein-subunits 11; HPETE, hydroperoxyeicosatetraenoic acid; IP3R, inositol 1,4,5-trisphosphate receptor; LOX, lipooxygenase; NGF, nerve growth factor; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PI3K, phosphatidylinositol 3-kinases; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipases A2; PLC, phospholipase C; PP2B, protein phosphatase 2B (Calcineurin (CN)); P38, mitogen-activated protein kinases; P450, cytochrome P450; Src, a family of proto-oncogenic tyrosine kinases, Rous sarcoma virus (RSV); Trk A, tyrosine kinase A; TRP, transient receptor potential (has TRPV, TRPM, TRPA, and TRPC subfamilies).


(Modified from Wang H, Woolf CJ. Pain TRPs. Neuron 2005;46:9-12.)


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Figure 2–6 Effect of the presence (panel A) and absence (panel B) of downstream regulatory element antagonistic modulator (DREAM) on nociceptive processing after noxious stimulation of the skin with a pin. In panel A, the prodynorphin gene is blocked by DREAM, and the nociceptive signal is transmitted by substance P (SP)-containing dorsal root neurons essentially unaltered through the spinal cord. This activated state is characterized by a large depolarizing potential and multiple spike discharges. Such activity subsequently activates systems governing descending regulatory control and thalamic nuceli, triggering the perception of pain. In panel B, DREAM has been knocked out, and the release of dynorphin from spinal cord interneurons becomes a prominent part of the nociceptive response. This inactivates spinal-projection neurons, leading to a greatly reduced excitatory response. Subsequently, there is almost complete inactivation of descending regulatory and pain-processing systems. In addition to raising issues related to the specific functions of DREAM, this simple scheme emphasizes the importance of neurophysiological research involving this model and hypotheses to guide drug design.


(From Vogt BA. Knocking out the DREAM to study pain.N Engl J Med 2002; 347: 362-364.)


Ectopic excitability, structural reorganization, and decreased inhibition are unique to neuropathic pain, whereas peripheral sensitization occurs in inflammatory pain and in some forms of neuropathic pain.


Pain transient receptor potential (TRP) ion channels are listed in Table 2.2 and illustrated in Figure 2-6. TRP ion channels are molecular gateways in sensory systems, an interface between the environment and the nervous system. Several TRPs transduce thermal, chemical, and mechanical stimuli into inward currents, an essential first step in eliciting thermal and pain sensations.



Table 2.2 Mammalian Sensory Transient Receptor Potentials (TRPs)

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Facet joint pain



Definition


The facet, or zygapophyseal, joint is the set of paired diarthrodial articulations between the posterior elements of the adjacent vertebrae.


Facet joints have been implicated as responsible for spinal pain in 39% of patients with neck pain, 34% of patients with thoracic pain, and 27% of patients with low back pain [1].



Innervations


The nerve roots are invested by pia mater and covered by arachnoid and dura as far as the spinal nerve. The dura of the dural sac continues around the roots as their dural sleeve, which blends with the epineurium of the spinal nerve (Fig. 2-7).


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Figure 2–7 Spinal nerves.


(From Schuenke M, Schulte E, Schumacher U, et al [eds]: Thieme Atlas of Anatomy: General Anatomy and Musculoskeletal System. Stuttgart, Thieme, 2006, p 62.)

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Aug 5, 2016 | Posted by in NEUROSURGERY | Comments Off on Current Understanding of Spinal Pain and the Nomenclature of Lumbar Disc Pathology

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