**7. Central sensitization leads to painful hypersensitivity**

Functional and structural changes of dorsal horn circuitry lead to pain hypersensitivity that is maintained independent of peripheral sensitization [38]. This central sensitization provides a mechanistic explanation for the sensory abnormalities that occur in both acute and chronic pain states, such as the expansion of hypersensitivity beyond the innervation territory of a lesion site, repeated stimulation of a constant magnitude leading to an increasing pain response, and pain outlasting a peripheral stimulus [39-41]. In healthy individuals, acute pain triggers central sensitization, but homeostatic sensitivity returns following clearance of the initial insult. In some individuals who develop neuropathic pain, genotype and environmental factors contribute to maintenance of central sensitization leading to spontaneous pain, hyperalgesia, and allodynia.

At the cellular level, potentiation or facilitation of synapses in the dorsal horn leads to central sensitization. The former is a type of homosynaptic strengthening whereby repeated neuro‐ transmitter release from a primary nociceptor leads to post-synaptic molecular remodeling in second order neurons, ultimately reducing the quantity of neurotransmitter required to generate an action potential (i.e. hyperalgesia). This process resembles long term potentiation (LTP), the molecular correlate of learning and memory, differing in the time-scale of associated post-synaptic changes and several molecular components [42]. Like LTP, potentiation of nociceptors in the dorsal horn is dependent on the post-synaptic function of ionotropic glutamate receptors (N-Methyl-D-aspartic acid receptors; NMDAR) suggesting that this may be a viable target for treating centrally maintained neuropathic pain.

Similarly, facilitation also results in a lowered activation threshold in second order neurons, but distinct from potentiation, the molecular changes occur in a nearby dendritic spine rather than the spine receiving the nociceptive input. If the nearby dendritic spine is a silent partner of an Aβ afferent, molecular changes that lower the threshold recruit this primary afferent into nociceptive circuitry resulting in the perception of pain from innocuous stimuli (i.e. allodynia).

**6. Pain circuits of the dorsal horn integrate information**

siological mechanisms in the development of neuropathic pain.

**7. Central sensitization leads to painful hypersensitivity**

be a viable target for treating centrally maintained neuropathic pain.

nuclei, so they will not be considered separately.

hyperalgesia, and allodynia.

A cross section of a spinal cord reveals morphologically and biochemically distinct layers of gray matter – Laminae of Rexed after the scientist who first described them – that integrate input from a variety of ascending and descending sources (Figure 2) [35]. Each layer forms a functional compartment containing a dense network of primary afferents, secondary projec‐ tion neurons, descending fibers, and interneurons with unique patterns of connectivity. The most superficial layers of the dorsal horn, laminae I and II, receive peripheral input almost exclusively from Aδ and C fibers while Aβ fibers innervate more medial laminae (III-IV)[36]. Lamina V contains wide dynamic range polymodal projection neurons that receive direct input from Aδ and Aβ fibers as well as indirect input from C fibers [36]. Thus, it appears there is both anatomical segregation (laminae I-IV) and integration (laminae V) of painful and nonpainful stimuli at the level of the spinal cord, providing the substrate for distinct pathophy‐

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

It should be noted that primary afferents originating from the orofacial region project to the trigeminal nucleus caudalis of the medulla rather than the dorsal horn of the spinal cord [37]. Similar organization, function, and pathophysiological mechanisms are observed in both

Functional and structural changes of dorsal horn circuitry lead to pain hypersensitivity that is maintained independent of peripheral sensitization [38]. This central sensitization provides a mechanistic explanation for the sensory abnormalities that occur in both acute and chronic pain states, such as the expansion of hypersensitivity beyond the innervation territory of a lesion site, repeated stimulation of a constant magnitude leading to an increasing pain response, and pain outlasting a peripheral stimulus [39-41]. In healthy individuals, acute pain triggers central sensitization, but homeostatic sensitivity returns following clearance of the initial insult. In some individuals who develop neuropathic pain, genotype and environmental factors contribute to maintenance of central sensitization leading to spontaneous pain,

At the cellular level, potentiation or facilitation of synapses in the dorsal horn leads to central sensitization. The former is a type of homosynaptic strengthening whereby repeated neuro‐ transmitter release from a primary nociceptor leads to post-synaptic molecular remodeling in second order neurons, ultimately reducing the quantity of neurotransmitter required to generate an action potential (i.e. hyperalgesia). This process resembles long term potentiation (LTP), the molecular correlate of learning and memory, differing in the time-scale of associated post-synaptic changes and several molecular components [42]. Like LTP, potentiation of nociceptors in the dorsal horn is dependent on the post-synaptic function of ionotropic glutamate receptors (N-Methyl-D-aspartic acid receptors; NMDAR) suggesting that this may

In addition to heterosynaptic strengthening, phenotypic changes or dendritic sprouting of Aβ fibers can lead to the incorporation of low threshold mechanoreceptors into pain circuitry.

**Figure 2. Neuronal architecture of the dorsal horn.** Laminae (represented by numerals I-VI) are morphologically and functionally distinct layers within the gray matter of the spinal cord. Lamina I primarily contains large projection neurons that send processes up the spinal cord towards higher brain regions. Lamina II, in contrast, is more heavily populated with interneurons, many of which supply inhibitory signals to lamina I projection neurons. Lamina V con‐ tains wide dynamic range neurons that receive primary input from multiple sensory modalities. Peripheral afferents project to distinct laminae. While Aδ and C fibers are associated with superficial laminae, Aβ fibers project more medi‐ ally. For a comprehensive review of dorsal horn circuitry see [36].

Two neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP) are normally exclusively expressed by Aδ and C fibers in the periphery. Following nerve injury, however, Aβ fibers begin to manufacture these neuropeptides [43]. Additionally, there is evidence to suggest that remodeling of Aβ dendritic arbors can create novel circuitry [44]. These changes all manifest as dynamic mechanical allodynia.

morphometry, and diffusion tensor MRI. In a comprehensive review, Apkarian and colleagues summarize this recent progress and propose a model that includes a temporal, as well as a spatial, cerebral representation of pain [53]. They've suggested that in the context of acute thermal pain activity in the anterior insula, nucleus accumbens (NAc), and mid-cingulum peak prior to the conscious perception of pain, the "anticipation", while perception is distinctly correlated with peak activity in the anterior cingulate, mid- and posterior insula, and portions of the dorsal striatum. Lastly, as the stimulus is extinguished bringing about "relief" regions

Neuropathic Pain: From Mechanism to Clinical Application

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

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Another significant finding led to the disentanglement of the neural coding for two distinct dimensions of a stimulus: the objective magnitude of an applied stimulus and an individual's subjective perception of stimulus intensity. Again using fMRI in the context of acute thermal pain, Baliki et. al. suggest that actual stimulus intensity is encoded by large portions of the cingulate and insular cortices while specific subsections of each, namely the anterior portion of the cingulate and the posterior insula, correlate strongly with subjective perception [56]. Thus it appears that pain perception follows a similar processing stream as other sensory modalities (e.g. vision, hearing, olfaction) wherein information about subjective magnitude is extracted by specific regions of the insular cortex [53]. These findings are beginning to lay the foundation for a clear and accurate representation of spatiotemporal coding of pain in the brain, with the ultimate goal of correlating neural activity with distinct cognitive and behav‐

**10. Morphological and functional changes in the brain are associated with**

Chronic pain conditions are associated with vast functional and structural changes of the brain, when compared to healthy controls, but it is currently unclear which comes first: does chronic pain cause distortions of brain circuitry and anatomy or do cerebral abnormalities trigger and/ or maintain the perception of chronic pain? Future studies will clarify these questions.

Brain abnormalities in chronic pain states include modification of brain activity patterns, localized decreases in gray matter volume, and circuitry rerouting [53]. Observation of overall brain activity patterns in a variety of chronic pain conditions has led to the discovery that spontaneous and evoked pain are uniquely represented in the brain [53]. Spontaneous pain associated with chronic back pain and PHN induce increased activity in the mPFC and amygdale while acute thermal pain and allodynia associated with PHN illicit larger responses in the thalamus and insula [53]. Similar activity patterns are observed in thermal and mechan‐ ical acute pain in healthy individuals and knee pain associated with osteoarthritis, all forms

Chronic pain conditions are associated with localized reduction in gray matter volume, and the topography of gray matter volume reduction is dictated, at least in part, by the particular pathology. Chronic back pain, for example, is associated with a loss of bilateral dorsolateral prefrontal cortex and unilateral thalamic gray matter [57] while irritable bowel syndrome

of the brainstem, in particular the periaqueductal grey (PAG), become active [53].

ioral functions.

**chronic pain**

of evoked pain [53].

In contrast to the gain-of-function changes that take place in Aβ fibers following injury, inhibitory descending and interneurons experience a sharp loss-of-function. This loss of inhibitory input releases the brake on neurotransmission and increases the excitatory current in the superficial dorsal horn [45]. Although there is evidence that excitotoxicity contributes to apoptotic loss of gamma-amino butyric acid (GABA)-ergic interneurons and descending inhibitory neurons of the rostroventral medulla [46, 47], it has been argued that injury-induced disinhibition is the result of attenuated efficacy of intact GABAergic interneurons that occurs independent of cell death [48-50]. Activation of microglia, resident macrophages of the nervous system, is a pathological hallmark of nervous system damage [51]. Release of brain-derived neurotrophic factor (BDNF) from activated microglia is necessary and sufficient to shift the anion reversal potential in lamina I projection neurons, reducing the effect of GABA in these neurons [52]. Specifically targeting BDNF or activated microglia may be a viable treatment for neuropathic pain.

## **8. Supraspinal nuclei interpret the signal**

Activation of peripheral nociceptors elicits a complex behavioral response that allows an organism to avoid the noxious stimulus immediately (by moving away from the source) and in the future (by enhanced learning and memory). To carry out the sum of these behaviors the pain circuit recruits a large number of cortical and subcortical regions that manage a variety of aspects of cognition and perception. Prominent examples include areas of the brain associated with motivation/reward, learning/memory, and somatosensation (reviewed in [53]). Classically, pain in the brain has been described in terms of a particular pattern of activation referred to as the "pain matrix". Areas of the matrix can be classified as belonging to one of two parallel pathways that control distinct aspects of pain: sensory discrimination (e.g. location, duration, and intensity) or affective/motivational (e.g. feelings of suffering and avoidance behaviors) [54, 55]. Increasing evidence gathered from rapidly evolving technology has suggested this description to be an oversimplification, however, as it applies uniquely to healthy individuals with experimentally induced acute pain [53]. Although useful, it is important for the future of pain research and treatment that we continue evaluate the current schematic, employing new technologies as they develop.
