, 2009). It is essential to shift focus from etiology to the reaction of the nervous system to the etiological pathology—to viewing neuropathic pain as a manifestation of pathological neural plasticity. The advantage of this approach is that it will lead to an explicit dual therapeutic focus aimed both at etiological factors and the forms of maladaptive plasticity they initiate. By definition, neuropathic pain involves damage to the nervous system (Jensen et al., 2011). Often, negative symptoms are the first indication of damage to the somatosensory system and can be detected by quantitative sensory testing as well as clinical examination and to a more limited extent, history/questionnaire.

The cause of negative symptoms in peripheral neuropathies is direct insult to primary sensory neurons. This may produce cell death or compromise transduction (due to terminal atrophy) or conduction (due to loss selleck products of peripheral axons) or transmission (due to loss of central terminals) of sensory information. Loss of function can manifest across the whole sensory spectrum (e.g., global numbness after a traumatic nerve injury) or it can affect specific modalities (Freeman, 2009). For example, an elevated heat threshold due to degeneration of intraepithelial C-fibers is a common early manifestation of peripheral diabetic DNA Damage inhibitor neuropathy

(Said, 2007) and in chemotherapy-induced neuropathies, where sensory but not motor axons show mitochondrial damage leading to hypoesthesia (Xiao et al., 2011). Many patients with neural damage only have negative symptoms, Phosphatidylinositol diacylglycerol-lyase some though, also have positive symptoms because particular pathological processes are engaged that increase pain sensitivity or drive spontaneous activation of the nociceptive pathway. Peripheral sensitization most characteristically occurs after peripheral inflammation and comprises a reduction in threshold and an increase in the excitability of the peripheral terminals of nociceptors in response to sensitizing inflammatory mediators. This results in innocuous stimuli at the

site of inflammation, such as light touch, warm or cool temperatures, being perceived as painful (allodynia), and stimuli that usually are felt as uncomfortable or slightly painful, such as a pinprick, becoming extremely painful (hyperalgesia) in the primary area of inflammation. However, peripheral sensitization can also occur after nerve lesions in the presence (peripheral neuritis) and absence of tissue inflammation, and thereby can contribute to pain hypersensitivity within the innervation zone of an affected nerve (Figure 3). External mechanical, thermal, and chemical stimuli are converted into voltage changes in sensory neurons by ion channels that respond to specific environmental stimuli. After nerve injury, peripheral sensitization results from reduced thresholds for activation these transducer channels together with nerve injury induced changes in sodium and potassium channels.