Causalgia and phantom limb pain are examples of pain that occur as a result of damage to a peripheral nerve. Causalgia typically arises after a traumatic injury to a peripheral nerve. Despite a reduction in evoked pain, individuals may experience severe pain in the area supplied by the damaged nerve. Treating this pain can be challenging, even with potent pain-relieving medications. The pain is partly caused by spontaneous activity in dorsal root ganglion cells, which may be due to an increase in Na+ channels. Sympathetic neural activity may also contribute to the pain, as blocking the sympathetic nerves can provide relief. Sympathetic involvement may be related to damaged sympathic postganglionic axons growing into the dorsal root ganglia, accompanied by an increase in adrenoreceptors in primary afferent neurons. Phantom limb pain, on the other hand, occurs in some individuals following traumatic amputation. This pain is not caused by the activation of pain receptors in the area where the pain is felt, as these receptors are no longer present.

Central pain, characterized by severe spontaneous pain, can occur as a result of lesions in the thalamus or other parts of the spinothalamocortical pathway. Interestingly, while these lesions can interrupt the nociceptive pathway and reduce pain caused by peripheral stimulation, they can also lead to trauma-induced pain due to neural damage. The mechanism behind this pain is not well understood, but it appears to involve changes in the activity and response properties of more distant neurons in the nociceptive system.

Understanding the transduction processes of the somatosensory system has been challenging due to various factors. The main transduction process occurs at the specialized endings of sensory neuron axons, specifically those found in the dorsal root ganglia and trigeminal ganglia cells. These endings have channels that can be activated by mechanical, thermal, and/or chemical stimuli. This activation allows for the flow of current, which generates the local generator potential. The generator potential then triggers spikes in the afferent fiber. However, the presence of somatosensory axons throughout the body at low densities makes it difficult to isolate and study the proteins involved in transduction.

Complicating matters further, the generator potential can be influenced by various voltage-gated channels, both excitatory (such as Na+ and Ca++ channels) and inhibitory (such as K+ channels). Additionally, the axon terminal is often encapsulated, and the properties of this accessory structure can modify the transduction process. This modification can occur passively due to the mechanical characteristics of the capsule or actively through the release of neurotransmitters by accessory cells in response to a stimulus. Merkel cells are an example of such accessory cells that have mechanosensitive channels and release neurotransmitter.

While it was previously believed that ASIC (acid-sensing ion channel) proteins were responsible for cutaneous mechanoactivated currents, recent evidence suggests otherwise. Knockdown of ASIC proteins does not affect the mechanoactivated currents in dorsal root ganglion cells, indicating that they are not the channels responsible for cutaneous mechanotransduction. However, these proteins may still play a modulatory role in the transduction process, as their knockdown mutants exhibit altered touch and pain sensitivity.
Examples of pain secondary to damage to a peripheral nerve are causalgia and phantom limb pain. Causalgia may develop after traumatic damage to a peripheral nerve. Even though evoked pain is reduced, severe pain may develop in the area innervated by the damaged nerve. This pain may be very difficult to treat, even with strong analgesic drugs. The pain is caused in part by spontaneous activity that develops in dorsal root ganglion cells; such activity may be attributed to upregulation of Na+ channels. In some cases the pain seems to be maintained by sympathetic neural activity, because a sympathetic nerve block may alleviate the pain. Sympathetic involvement may relate to the sprouting of damaged sympathic postganglionic axons into the dorsal root ganglia, and it may be accompanied by upregulation of adrenoreceptors in primary afferent neurons. Phantom limb pain follows traumatic amputation in some individuals. Such phantom pain is clearly not caused by activation of nociceptors in the area in which pain is felt, because these receptors are no longer present.
Lesions of the thalamus or at other levels of the spinothalamocortical pathway may cause central pain, which is a severe spontaneous pain. However, interruption of the nociceptive pathway by the same lesion may simultaneously prevent or reduce the pain evoked by peripheral stimulation. The mechanism of such trauma-induced pain caused by neural damage is poorly understood. The pain appears to depend on changes in the activity and response properties of more distant neurons in the nociceptive system.
Transduction in the Somatosensory System
Unraveling the transduction processes for the somatosensory system has proven difficult because of a variety of factors. The heart of the transduction process occurs at the specialized endings of the peripheral branch of the axon of the sensory neuron (dorsal root ganglia and trigeminal ganglia cells). These endings have channels that are activated by mechanical, thermal, and/or chemical stimuli and that allow the current flow that underlies the local generator potential (see
Fig. 5.13 ). The generator potential then triggers spikes in the afferent fiber (see
Fig. 5.14 ). However, the fact is that somatosensory axons are found throughout the body at low densities, making purification of the proteins difficult (e.g., compare with the retina, in which photoreceptors are packed at high density onto a small surface).
Complicating matters, the generator potential can be modified by a host of voltage-gated channels, both excitatory (e.g., Na+ and Ca++ channels) and inhibitory (K+ channels). Moreover, as described earlier, in many cases the axon terminal is encapsulated (e.g., Pacinian corpuscles), and the properties of this accessory structure modify the transduction process. They may do so passively, as a result of the mechanical characteristics of the capsule, or actively by having the accessory cells release transmitter in response to a stimulus. An example of the latter is Merkel cells, where recent evidence suggests the Merkel cells and the axon innervating them both have mechanosensitive channels and the Merkel cells release neurotransmitter.
Despite these complications, using a number of approaches, our knowledge of somatosensory transduction processes has begun to increase rapidly.
Until recently, ASIC (acid-sensing ion channel) proteins, which belong to the DEG/ENaC family, had been thought to be the channel proteins underlying the cutaneous mechanoactivated currents, because homologs of these proteins underlie the touch sensation in invertebrates such as Caenorhabditis elegans, and because some ASIC proteins are highly expressed in dorsal root ganglion cells. However, the mechanoactivated currents in dorsal root ganglion cells are not affected by knockdown of the ASIC proteins, indicating that they are not the channel underlying cutaneous mechanotransduction. Nevertheless, touch and pain sensitivity is altered in such knockdown mutants, so they may still play a modulatory role in the transduction process.