**3. Anatomical overview of pain as a somatosensory modality**

remains ineffective and insufficient [16]. The lack of translational efficiency may be due to inadequate animal models that do not faithfully recapitulate human disease or from biological differences between rodents and humans [16]. Whatever the cause, the translational gap necessitates a bridge between clinicians and basic researchers in order to move from the clinic

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

In an attempt to increase the efficacy of medical treatment for neuropathic pain, clinicians and researchers have been moving away from an etiology based classification towards one that is mechanism based. It is current practice to diagnose a person who presents with neuropathic pain according to the underlying etiology and lesion topography [17]. However, this does not translate to effective patient care as these classification criteria do not suggest efficacious treatment. A more apt diagnosis might include a description of symptoms and the underlying pathophysiology associated with those symptoms. This chapter attempts to define neuropathic pain at the cellular and molecular level, as seen by a laboratory scientist, and then describe how the manifestations of these pathophysiologic changes are observed in the clinic, as seen by a clinician. It will then discuss a merger of the two points of view and suggest how this can

Neuropathic pain has been defined by the International Association for the Study of Pain (IASP) as "pain arising as the direct consequence of a lesion or disease affecting the somatosensory system" [18]. This is distinct from nociceptive pain – which signals tissue damage through an intact nervous system – in underlying pathophysiology, severity, and associated psychological comorbidities [13]. Individuals who suffer from neuropathic pain syndromes report pain of higher intensity and duration than individuals with non-neuropathic chronic pain and have

Any trauma to the somatosensory system appears to have the capacity to cause a neuropathic pain syndrome; yet the presence of any individual pathology does not guarantee the develop‐ ment of neuropathic pain, highlighting the importance of genetic and environmental factors as well as individual disease pathogenesis. To further complicate matters, individuals with seemingly identical diseases who both develop neuropathic pain may experience distinct abnormal sensory phenotypes. This may include a loss of sensory perception in some modali‐ ties and increased activity in others. Often a reduction in the perception of vibration and light touchiscoupledwithpositivesensorysymptoms suchasparesthesia,dysesthesia,andpain[20]. Pain may manifest as either spontaneous, with a burning or shock-like quality, or as a hypersen‐ sitivity to mechanical or thermal stimuli [21]. This hypersensitivity takes two forms: allodynia, painthatisevokedfromanormallynon-painfulstimulus,andhyperalgesia,anexaggeratedpain response from a moderately painful stimulus. For a more extensive list of sensory signs and symptoms associated with neuropathic pain see Table 1. Ultimately, the path towards effica‐ cious treatment of chronic pain will include a clear understanding of how certain pathophysio‐ logic changes lead to specific sensory signs and symptoms. This will allow clinicians to translate

significantly increased incidence of depression, anxiety, and sleep disorders [13, 19].

to the laboratory and back into the clinic.

**2. Definition of neuropathic pain**

lead to better patient care through more effective treatment.

At the turn of the 20th century Charles Sherrington proposed the concept of pain-specific neural circuitry and deemed neurons within this circuit "nociceptors" [22]. This "specificity theory" of pain was competing for favor with the prevailing "pattern theory" which held that pain was encoded by the same low-threshold sensory nerve endings that transmit information about vibration and light touch through high frequency stimulation and central summation [23]. It is now clear, as Sherrington proposed that the sensation of pain is encoded by a unique set of peripheral and central neurons whose primary purpose is to alert the organism to a potentially dangerous situation.

The nociceptive system detects noxious stimuli (i.e. that are of a sufficient magnitude to cause bodily injury) and elicits appropriate avoidance behaviors. Detection begins with free nerve endings in the skin or viscera that carry specialized membrane receptors capable of converting high magnitude chemical, mechanical, or thermal energy into an electrical impulse. The impulse is carried from the periphery to the dorsal horn of the spinal cord where neurotrans‐ mitter release relays the activity to second order neurons. Here, signals from the periphery are integrated with information from descending sources that modulate nociceptive circuitry in a manner that is dependent on the environmental context. The sum of this exchange is carried by secondary projection neurons to supraspinal nuclei which interpret the signal and create the conscious perception of pain.

The nociceptive circuit is not static, however; there is tremendous plasticity, from the periphery to the neocortex, which modulates the perception of pain to reflect the physiological needs of the organism and optimize survival. This is best understood by considering two examples of hypo- and hyper- sensitivity to pain: a time of war and an illness, respectively. Perceiving pain during a period of intense stress, such as wartime, would decrease chances of survival by increasing vulnerability to a more immediate threat. Conversely, in a low stress environment activation of the inflammatory response as a result of illness or injury sensitizes nociceptors leading to pain hypersensitivity, rest, and healing. Neuropathic pain, therefore, can be considered an inappropriate hijacking of inherent neuronal plasticity to promote hypersensi‐ tivity in contexts where it is not beneficial.
