Michael W. Salter
The International Association for the Study of Pain defines neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”1 Certain mechanisms such as peripheral sensitization of nociceptors or central sensitization (see chapters 5 and 6), which are known to occur in acute nociceptive pain, can participate in neuropathic pain in addition to the mechanisms appearing specifically after nerve injury. After a traumatic event involving peripheral neural tissues, spontaneous and evoked hyperalgesia can often be observed. This is frequently associated with allodynia, anesthesia, dysesthesia, or hypoesthesia (see chapter 1). A lesion of the inferior alveolar nerve following avulsion of the third molar is an example of such a traumatic event in the orofacial area. Models of chronic or persistent pain triggered by these nerve lesions exist in animals. A lesion of spinal or trigeminal (V) sensory nerves can lead to increased receptive field (RF) size and responses to noxious stimuli, decreased activation thresholds, abnormal spontaneous discharges of spinal or V central neurons, and pain behavior in animals.2 Analogous neuronal changes can also be observed after even more discrete lesions such as a pulpotomy.3,4 Such neuroplastic changes may explain certain persistent pain conditions such as posttraumatic dysesthesia or atypical odontalgia, which can last for months or years after endodontic therapy of a tooth that had previously been symptom-free.5
These clinical and experimental effects of neural damage involve several mechanisms that are described in this chapter.
Ectopic Impulses from Damaged Primary Afferent Nerve Fibers
Several types of injury to primary afferents can lead to persistent pain and are common in the orofacial region.2,6 Incisions, crush injury, or stretching or destruction by metabolic (eg, diabetes), chemical (eg, chemotherapy), or infective (eg, virus) diseases can lead to anterograde and retrograde degeneration as well as regeneration of the nerve fibers. Disorganization of the myelin sheath around myelinated fibers is another possible, sometimes concomitant, occurrence. As a result, abnormal activity or bursts of impulses that do not originate from nociceptor terminals may occur. These ectopic discharges may originate from large-diameter afferent fibers, small-diameter afferent fibers, the site of nerve damage, a focus of demyelinization, or even the cell body in the sensory ganglion. In addition, axon sprouting may occur following severance of peripheral nerve fibers. A great number of unmyelinated or thinly myelinated nerve fibers grow from the cut nerve trunk toward the original peripheral site. These sprouts can generate spontaneous discharges within days in the case of the myelinated fibers and within weeks for the unmyelinated fibers. These abnormal discharges persist until the target tissue is reached. If this does not occur because of the loss of the target or because of the presence of an obstacle, a neuroma can result. In this situation, many axons die; but those that remain may form a tangled mass of nervous tissue in conjunction with proliferated Schwann cells, which ensheath unmyelinated as well as myelinated axons of primary afferents.
In the neuroma, both myelinated and unmyelinated nerve fibers develop abnormal spontaneous and provoked activity, particularly following light tactile stimulation. A neuroma may also exhibit ephaptic transmission, which appears when two or more adjacent demyelinated or unmyelinated fibers of the damaged nerve form abnormal connections between or among them. Nerve fibers of all sizes may be involved. This ephaptic transmission process allows a very effective, though abnormal, transfer of impulses from one fiber type to another. Reverberating impulses may also be generated from focally demyelinated fibers. It has been shown that prolonged high-frequency discharges of “reflected” impulses can be generated by repeated stimulation, and impulses can be propagated both orthodromically (ie, toward the central nervous system [CNS]) and antidromically (ie, toward the peripheral tissues innervated by the fiber) from the demyelinated site. The nervi nervorum, which provides the innervation of the connective tissue sheath around the nerve, is thought by some authors to directly induce “nerve trunk pain” following damage to the nerve sheath, which may in turn induce discharge of impulses. Local inflammatory reactions and local sprouting may also occur around or from the nervi nervorum.
Involvement of the Sympathetic Nervous System
The relation between pain and the sympathetic nervous system has been known for a long time, and the clinical concept of sympathetically maintained pain reflects the belief that some pain conditions can be maintained by the sympathetic system.7,8 The role of the sympathetic system is revealed by increased pain following the administration of agents that affect this system, decreased pain after administration of sympathetic antagonists (eg, that block α-adrenoreceptors) or guanethidine (a substance that acts by first releasing and then depleting norepinephrine from the sympathetic efferent terminals), or increased pain after the triggering of a sympathetic reflex. Moreover, one of the most common procedures in the treatment of these conditions is a local anesthetic block of the sympathetic ganglion, including the stellate ganglion in the case of some orofacial pains.
The underlying pathophysiologic mechanism seems to depend on a functional relationship between efferents of the sympathetic nervous system and somatic afferents, at least in the spinal so-matosensory system. It has been shown that following peripheral spinal nerve injury, somatic primary afferent fibers, either myelinated or unmyelinated, express or upregulate α-adrenoreceptors. At the same time, sympathetic efferents become coupled with the afferents. Synaptic contacts can be established with the fiber at the lesion site or with the soma. For example, after a partial lesion of a spinal nerve, electric stimulation of a sympathetic trunk may activate or sensitize some nociceptors, and the somatic afferents may become sensitive to systemic catecholamines. Alternatively, following nerve injury, sympathetic efferent terminals sprout and form arborizations around some cell bodies in the spinal dorsal root ganglion; sympathetic efferent terminals are not normally present in this location. Some allodynia observed after peripheral axotomy is thought to be due to such coupling between sympathetic efferents and dorsal root ganglion neurons related to A-β fibers.8 Whether this coupling occurs in the V ganglion is unclear.
Peripheral injury may also be associated with morphologic modification at the central endings of the primary afferent fibers. Sectioning a peripheral nerve results in reorganization of the central branches of axonal endings of A-β primary afferents. After sprouting, the terminals that were previously distributed in layers III and IV of the spinal dorsal horn may make synaptic contacts in more superficial layers of the dorsal horn. This could explain some types of allodynia, if the terminals of A-β afferents that transmit tactile messages were to make contact with nociceptive neurons present in these superficial layers.2 It is likely that analogous brain stem changes occur in the V subnucleus caudalis.
Phenotypic Changes in Primary Afferents and Dorsal Horn Neurons