**4. Peripheral nociceptors detect a noxious stimulus**

Noxious stimuli are perceived by small diameter peripheral neurons whose free nerve endings are distributed throughout the body. These neurons are distinct from, although anatomically proximal to, the low threshold mechanoreceptors responsible for the perception of vibration and light touch. Both low and high threshold afferents are pseudounipolar neurons of the dorsal root and trigeminal ganglion with peripheral terminals that extend into the skin/viscera and central terminals that extend into the gray matter of the spinal cord or trigeminal nucleus caudalis depending on whether they originated from the body or face, respectively. Low threshold afferents, or Aβ fibers, can be distinguished from nociceptors by biochemical and electrophysiological properties. Aβ neurons are large diameter, heavily myelinated, and fast conducting fibers, while nociceptors fall into one of two functionally distinct categories: lightly myelinated, medium diameter (1-5 µm) Aδ fibers that mediate a sharp, well localized "first" pain and unmyelinated, small diameter (0.2 – 1.5µm) C fibers that mediate a duller, anatomi‐ cally diffuse "second" pain. Together with Aα fibers (which will not be considered here) Aβ, Aδ, and C fibers constitute the somatosensory system.

In addition to hypersensitivity, individuals with neuropathic pain frequently experience ongoing spontaneous pain as a major source of discomfort and distress. Following trauma to the peripheral nerve, ectopic activity was observed in primary nociceptors in the periphery, suggesting this to be the major source of spontaneous pain [32]. In healthy individuals, a quiescent neuron will only generate an action potential when presented with a stimulus of sufficient magnitude to cause membrane depolarization. Following nerve injury, however, significant changes in ion channel expression, distribution, and kinetics lead to disruption of the homeostat‐ ic electric potential of the membrane resulting in oscillations and burst firing. This manifests as spontaneous pain that has a shooting or burning quality [31]. Three types of ion channels seem

channels (VGSC; i.e. Nav1.8, Nav1.6, Nav1.1, Nav1.9) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Figure 1) [31]. There is reasonable evidence to suggest that individual ion channels contribute to specific neuropathic pain symptoms; for example Nav1.8 plays a role in cold-induced allodynia (for review see [33, 34]). The exact nature and extent of this relationship is unclear, but it provides an intriguing therapeutic possibility: unambiguous pharmacologic ion channel blockers to relieve individual sensory symptoms with minimal

**Figure 1. Pathophysiological changes associated with a primary afferent nociceptor.** A pseudounipolar C-fiber detects a stimulus in the skin or viscera, and an action potential (AP) is propagated along the axon prompting neuro‐ transmitter (NT) release from the central terminal. Following nerve injury, modulation and modification of molecular components can lead to painful hypersensitivity to stimuli as well as spontaneous or ongoing pain. For simplification we portray a unidirectional flow of information, but it's interesting to note that generation of an AP or NT release as

channels (TRESK and TREK-2), voltage gated sodium

Neuropathic Pain: From Mechanism to Clinical Application

http://dx.doi.org/10.5772/55277

7

to mediate this effect: two-pore domain K+

unintended effects allowing pain relief without global numbness.

well as the associated pathophysiological changes can occur at either terminal.

### **5. Membrane receptors capture energy and modulate excitability**

As mentioned above, the purpose of these primary afferents is to detect noxious stimuli in the environment, for example a hot stove, or within the body as in an acidic or chemically unbalanced stomach. This requires the translation of chemical or high magnitude mechanical and thermal energy into an electrical impulse, a function carried out by a myriad of specialized receptors and ion channels (e.g. sodium and potassium channels, G-coupled protein receptors, receptor tyrosine kinases) that are embedded in the neuronal membrane. In addition to primary detection of the stimulus, these specialized receptors/ion channels also play an important role in nociceptive plasticity by regulating membrane excitability and dictating the magnitude of stimulus required to generate an action potential.

A major breakthrough in understanding how nociceptors detect environmental stimuli came with the discovery of the transient receptor potential (TRP) family of nonselective cation channels [24]. These membrane-bound receptors – for the first time – provided a substrate by which noxious energy could elicit neuronal depolarization. Each of the twenty-eight known TRP family members has a unique profile of activation that includes thermal and chemical stimuli [25]. The most well-characterized TRP channel, TRPV1, is activated by temperatures >42°C and the chemical compound capsaicin (the "hot" component of chili peppers) under normal physiological conditions [24]. In pathological states, TRPV1 has been implicated in pain hypersensitivity in models of inflammation, diabetic neuropathy [26, 27], partial nerve injury [28, 29], and chemotherapy- induced painful neuropathy [30]. Mechanistically, TRPV1 mediated hypersensitivity occurs as the result of changes in the expression, trafficking, and activation potential of TRPV1 following nerve injury [31]. Components of the inflammatory soup can modify TRPV1 by either direct allosteric modulation or indirect modification. For example, protons may bind directly to the extracellular domain, or stimulation of membrane bound receptor tyrosine kinases may trigger intracellular signaling cascades that result in phosphorylation of an intracellular domain. These physical modifications lead to altered activation kinetics and ultimately a lowered thermal or mechanical threshold for individual nociceptors (Figure 1) [31]. The behavioral correlate of a cellular lowering of threshold is hypersensitivity to thermal or mechanical stimuli i.e. allodynia and hyperalgesia.

In addition to hypersensitivity, individuals with neuropathic pain frequently experience ongoing spontaneous pain as a major source of discomfort and distress. Following trauma to the peripheral nerve, ectopic activity was observed in primary nociceptors in the periphery, suggesting this to be the major source of spontaneous pain [32]. In healthy individuals, a quiescent neuron will only generate an action potential when presented with a stimulus of sufficient magnitude to cause membrane depolarization. Following nerve injury, however, significant changes in ion channel expression, distribution, and kinetics lead to disruption of the homeostat‐ ic electric potential of the membrane resulting in oscillations and burst firing. This manifests as spontaneous pain that has a shooting or burning quality [31]. Three types of ion channels seem to mediate this effect: two-pore domain K+ channels (TRESK and TREK-2), voltage gated sodium channels (VGSC; i.e. Nav1.8, Nav1.6, Nav1.1, Nav1.9) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Figure 1) [31]. There is reasonable evidence to suggest that individual ion channels contribute to specific neuropathic pain symptoms; for example Nav1.8 plays a role in cold-induced allodynia (for review see [33, 34]). The exact nature and extent of this relationship is unclear, but it provides an intriguing therapeutic possibility: unambiguous pharmacologic ion channel blockers to relieve individual sensory symptoms with minimal unintended effects allowing pain relief without global numbness.

dorsal root and trigeminal ganglion with peripheral terminals that extend into the skin/viscera and central terminals that extend into the gray matter of the spinal cord or trigeminal nucleus caudalis depending on whether they originated from the body or face, respectively. Low threshold afferents, or Aβ fibers, can be distinguished from nociceptors by biochemical and electrophysiological properties. Aβ neurons are large diameter, heavily myelinated, and fast conducting fibers, while nociceptors fall into one of two functionally distinct categories: lightly myelinated, medium diameter (1-5 µm) Aδ fibers that mediate a sharp, well localized "first" pain and unmyelinated, small diameter (0.2 – 1.5µm) C fibers that mediate a duller, anatomi‐ cally diffuse "second" pain. Together with Aα fibers (which will not be considered here) Aβ,

6 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

**5. Membrane receptors capture energy and modulate excitability**

As mentioned above, the purpose of these primary afferents is to detect noxious stimuli in the environment, for example a hot stove, or within the body as in an acidic or chemically unbalanced stomach. This requires the translation of chemical or high magnitude mechanical and thermal energy into an electrical impulse, a function carried out by a myriad of specialized receptors and ion channels (e.g. sodium and potassium channels, G-coupled protein receptors, receptor tyrosine kinases) that are embedded in the neuronal membrane. In addition to primary detection of the stimulus, these specialized receptors/ion channels also play an important role in nociceptive plasticity by regulating membrane excitability and dictating the

A major breakthrough in understanding how nociceptors detect environmental stimuli came with the discovery of the transient receptor potential (TRP) family of nonselective cation channels [24]. These membrane-bound receptors – for the first time – provided a substrate by which noxious energy could elicit neuronal depolarization. Each of the twenty-eight known TRP family members has a unique profile of activation that includes thermal and chemical stimuli [25]. The most well-characterized TRP channel, TRPV1, is activated by temperatures >42°C and the chemical compound capsaicin (the "hot" component of chili peppers) under normal physiological conditions [24]. In pathological states, TRPV1 has been implicated in pain hypersensitivity in models of inflammation, diabetic neuropathy [26, 27], partial nerve injury [28, 29], and chemotherapy- induced painful neuropathy [30]. Mechanistically, TRPV1 mediated hypersensitivity occurs as the result of changes in the expression, trafficking, and activation potential of TRPV1 following nerve injury [31]. Components of the inflammatory soup can modify TRPV1 by either direct allosteric modulation or indirect modification. For example, protons may bind directly to the extracellular domain, or stimulation of membrane bound receptor tyrosine kinases may trigger intracellular signaling cascades that result in phosphorylation of an intracellular domain. These physical modifications lead to altered activation kinetics and ultimately a lowered thermal or mechanical threshold for individual nociceptors (Figure 1) [31]. The behavioral correlate of a cellular lowering of threshold is

hypersensitivity to thermal or mechanical stimuli i.e. allodynia and hyperalgesia.

Aδ, and C fibers constitute the somatosensory system.

magnitude of stimulus required to generate an action potential.

**Figure 1. Pathophysiological changes associated with a primary afferent nociceptor.** A pseudounipolar C-fiber detects a stimulus in the skin or viscera, and an action potential (AP) is propagated along the axon prompting neuro‐ transmitter (NT) release from the central terminal. Following nerve injury, modulation and modification of molecular components can lead to painful hypersensitivity to stimuli as well as spontaneous or ongoing pain. For simplification we portray a unidirectional flow of information, but it's interesting to note that generation of an AP or NT release as well as the associated pathophysiological changes can occur at either terminal.
