Pain Mechanisms and Their Importance in Clinical Practice and Research
Isabelle Decosterd
Clifford J. Woolf
After great pain, a formal feeling comes
The Nerves sit ceremonious, like Tombs
The stiff Heart questions was it He, that bore,
And Yesterday, or Centuries before?
—Emily Dickinson, 1830–1886
It has become increasingly clear from animal models and from preclinical and clinical studies that multiple mechanisms operating at different sites and with different temporal profiles induce chronic pain syndromes. Identification of these mechanisms may provide the best lead to effective treatment of pain. Although primary disease factors initiate pain mechanisms, it is the molecular and structural reorganization of the pain pathways and not the disease factors that produce chronic pain. The identification of etiologic or disease/causative factors is obviously important, but it is also essential to differentiate them from pain mechanisms. Because a particular disease may activate several different distinct pain mechanisms, a disease-based classification is useful primarily for disease-modifying therapy, but less so for pain therapy. Similarly, symptoms are not equivalent to mechanisms, although they may reflect them. The same symptom may be produced by a number of different mechanisms, and a single mechanism may elicit different symptoms.
In this chapter, we propose a new way of analyzing pain on the basis of the current understanding of pain mechanisms and show its implications for assessing pain in individual patients and for evaluating new forms of diagnosis and therapy.
I. FUNDAMENTAL PAIN MECHANISMS
1. Response to Acute Painful Stimuli
Acute pain is initiated by a subset of highly specialized primary neurons, the high-threshold nociceptors, and innervating peripheral tissues (i.e., skin, muscle, bone, and viscera). The peripheral terminals of these sensory neurons are adapted so as to be activated only by intense or potentially damaging peripheral noxious stimuli. These afferents, including both unmyelinated C fibers and light-myelinated Aδ fibers, are functionally distinct from the low-threshold sensory fibers, which are normally activated only in response to nondamaging, low-intensity, innocuous stimuli (A fibers). Nociceptor transduction mechanisms involve activation of temperature ion channel transducers of the transient receptor potential (TRP) family [e.g., the heat/capsaicin vanilloid TRP type 1 (TRPV1) sensor, the heat vanilloid TRP type 2 (TRPV2) sensor, the cold/menthol sensor melastatin TRP type 8 (TRPM8), and the cold TRP ankyrin transmembrane protein 1 (TRPA1, also mentioned as ANKTM1) sensor], sodium and potassium channels sensitive to intense mechanical deformation or stretch of the membrane [e.g., mammalian degenerin channel (MDEG), K+ channel type 1 (TREK-1)], or chemosensitive ion channels and metabotropic receptors [e.g., acid-sensing ionic channels (ASICs), TRPV1, bradykinin receptors BK1 and BK2, ATP-gated ion channel type 3 (P2X3), ATP G-protein coupled receptors type 2 (P2Y2), prostaglandin E-receptor (EP-R)] that are activated by protons, purines, amines, peptides, growth factors, prostaglandins, and cytokines released from damaged tissue or inflammatory cells. Activation of the ion channel transducers leads to inward currents in the peripheral terminal and thereby to action-potential generation, which is conducted from the periphery to the spinal cord. Invasion of the central axon terminals of primary afferents in the superficial dorsal horn by action potentials leads to an inrush of calcium and a synaptic release of the excitatory amino acid transmitter glutamate. Glutamate generates fast synaptic potentials in dorsal horn neurons via the α-amino-3 hydroxy-5 methyl-4 isoxazole proprionic acid receptor (AMPA)/kainate ionotropic receptors, and this is boosted and prolonged by the N-methyl-D-aspartate (NMDA) receptor–ion channel. These synaptic potentials encode information about the onset, intensity, quality, location, and duration of the peripheral noxious stimulus. The input is conveyed, after considerable excitatory and inhibitory processing in the dorsal horn, via projection neurons to higher centers where it is integrated in the cortex into an acute pain sensation. Such nociceptive pain (normal pain sensitivity) has an adaptive protective role, both warning of potential tissue damage and eliciting strong reflex and behavioral avoidance responses.
2. Peripheral Sensitization
The sensitivity of the peripheral terminal of nociceptors is not fixed, and its activation either by repeated peripheral stimulation or by changes in the chemical milieu of the terminal can sensitize the primary sensory neuron. This phenomenon is referred to as peripheral sensitization. Peripheral sensitization reflects
changes both in transduction channel thresholds and kinetics and in terminal membrane excitability. These changes occur in response to the direct activation of the transduction channels, to the process of autosensitization, and to extrinsic sensitizing stimuli such as inflammatory mediators. Autosensitization of TRPV1, for instance, involves entry of calcium through the ion channel, leading to activation of protein kinase C within the cytoplasm of the peripheral terminal. Protein kinase C (PKC) in turn phosphorylates TRPV1, leading to a reduction in its threshold for activation from 43°C to 38°C. Heterosensitization is driven by sensitizing agents such as prostaglandin E2, bradykinin, 5-HT, and nerve growth factors that activate, via their G-protein–coupled or tyrosine kinase receptors, intracellular kinases that phosphorylate and thereby augment the activity state of voltage-gated sodium channels such as Nav1.8, a sensory neuron–specific sodium channel.
changes both in transduction channel thresholds and kinetics and in terminal membrane excitability. These changes occur in response to the direct activation of the transduction channels, to the process of autosensitization, and to extrinsic sensitizing stimuli such as inflammatory mediators. Autosensitization of TRPV1, for instance, involves entry of calcium through the ion channel, leading to activation of protein kinase C within the cytoplasm of the peripheral terminal. Protein kinase C (PKC) in turn phosphorylates TRPV1, leading to a reduction in its threshold for activation from 43°C to 38°C. Heterosensitization is driven by sensitizing agents such as prostaglandin E2, bradykinin, 5-HT, and nerve growth factors that activate, via their G-protein–coupled or tyrosine kinase receptors, intracellular kinases that phosphorylate and thereby augment the activity state of voltage-gated sodium channels such as Nav1.8, a sensory neuron–specific sodium channel.
3. Central Sensitization and Modulation
In addition to changes in the sensitivity of the nociceptor peripheral terminal, an augmentation of nociceptive synaptic transmission in the dorsal horn of the spinal cord occurs and contributes to increased pain sensitivity, the phenomenon of central sensitization.
Intense input from nociceptors to the spinal cord evokes an immediate sensation of pain that lasts for the duration of the noxious stimulus and reflects direct activation of an action-potential output in projection neurons. Such input, however, also induces an activity-dependent functional modulation of sensory processing in the dorsal horn that leads to pain hypersensitivity. This is called central sensitization. The increased excitability is triggered by the peripheral nociceptor input, releasing excitatory amino acid and neuropeptide neurotransmitters, which act on the spinal cord neuron postsynaptic receptors to produce synaptic currents, and to activate intracellular signal transduction cascades in these neurons. These processes include activation of several protein kinases (PKA and PKC), calcium/calmodulin-dependent protein kinase (CaMK), and the mitogen-activated protein kinases (MAPKs). Both serine/threonine and tyrosine kinases, by phosphorylating NMDA
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