Neuropathic pain occurs when something has gone terribly wrong with the normal protective mechanisms of nociception and pain
signaling. The International Association for the Study of Pain defines neuropathic pain as "pain caused by a lesion or disease
of the somatosensory nervous system."1
The easy part of this definition is "lesion," because it's something that can be identified via a history of trauma, surgery
(e.g., severing nerve trunks during amputation) or imaging (e.g., tumor or intervertebral disk herniation).
The much more difficult part of this definition has to do with "disease," because central and peripheral hypersensitization
characteristics of neuropathic pain involve biochemical and microanatomical changes below the sensitivity of any conventional
imaging to detect.
Sustained or intense nociception and damage to peripheral nerves considerably alters the dynamic of the usual pain machinery,
moving it from a physiologic, protective nature to a maladaptive one. The constant or exaggerated presence of inflammatory
and bioactive mediators at a peripheral site forms a "sensitizing soup" that creates relentless excitation of afferent nociceptors.
This construct of direct nerve damage can cause a tsunami of excitatory neuropeptides in the dorsal horn of the spinal cord.
Normally, stubborn N-methyl-D-aspartate calcium channels are thrown wide open. The resulting calcium influx into postsynaptic
interneurons elicits a cascade of signaling mechanisms involving protein kinase C, nitrous oxide, substance P and neurokinin
(NK-1) receptors (expression of the NK-1 receptor appears to also contribute to opioid-induced hyperalgesia and tolerance2 ), calcitonin gene-related peptide and more. Not only does the interneuron stay depolarized, but a phenotypic change may
be induced where it may not reset. Expressions of the c-fos, c-jun and Krox-24 genes transcribe new (probably aberrant) proteins that produce permanent microstructural changes of the neuron.
Furthermore, the afferent nociceptor can conduct a signal efferently, in an antidromic fashion. There, at the peripheral site
of original stimulus, further release of inflammatory mediators is elicited, recruiting and activating other previously innocent
bystanding nociceptors, further bombarding the dorsal horn with impulses.2 As the feedback loop persists, more and more cells express c-fos and other genes, nerve growth factor is stimulated into production (suspected to be from glial cells) and more interconnections
are made between types and locations of neurons in the spinal cord.3 And mere touch now can be perceived as pain.
These interconnections are not isolated to somatosensory neurons, for they've been shown to newly express adrenoceptors that
are activated by catecholamines. Sympathetic stimulation may then result in nociception4,5 and may in fact be central to the pathophysiology of some of the more intense refractory forms of neuropathic pain known
as complex regional pain syndrome. Moreover, neuropathic pain is associated with alterations in receptor location (more places on more axons) and sensitivity
to excitatory amino acids (greater) throughout the nervous system.6
Glial cells (astrocytes, microglia, oligodendrocytes) in the spinal cord, whose purpose was once thought to be merely structural
and macrophage-like in nature (i.e., providing synaptic architecture, host defense, and myelin, respectively), are now known
to also be highly integrated into the pain process, particularly regarding chronic and neuropathic pain.7 Recently, this was described as the tetrapartite synapse, which includes an astrocyte, microglial cell and the pre- and post-synaptic neuronal terminal.8
Glia are the predominate source of nerve growth factor, and a recently isolated chemokine, fractalkine, appears to be a neuron-glial
cell signal, activating glially dependent pain.9 Indeed, glia appear to play a primary role regarding synaptic strength, plasticity and sensitization in the spinal cord,
which exhibits substantial change under the influence of chronic or intense pain.10