This review deals with physiological and biological mechanisms of neuropathic pain,
that is, pain induced by injury or disease of the nervous system. Animal models of
neuropathic pain mostly use injury to a peripheral nerve, therefore, our focus is
on results from nerve injury models. To make sure that the nerve injury models are
related to pain, the behavior was assessed of animals following nerve injury, i.e.
partial/total nerve transection/ligation or chronic nerve constriction. The following
behaviors observed in such animals are considered to indicate pain: (a) autotomy,
i.e. self-attack, assessed by counting the number of wounds implied, (b) hyperalgesia,
i.e. strong withdrawal responses to a moderate heat stimulus, (c) allodynia, i.e.
withdrawal in response to non-noxious tactile or cold stimuli. These behavioral parameters
have been exploited to study the pharmacology and modulation of neuropathic pain.
Nerve fibers develop abnormal ectopic excitability at or near the site of nerve injury.
The mechanisms include unusual distributions of Na(+) channels, as well as abnormal
responses to endogenous pain producing substances and cytokines such as tumor necrosis
factor alpha (TNF-alpha). Persistent abnormal excitability of sensory nerve endings
in a neuroma is considered a mechanism of stump pain after amputation. Any local nerve
injury tends to spread to distant parts of the peripheral and central nervous system.
This includes erratic mechano-sensitivity along the injured nerve including the cell
bodies in the dorsal root ganglion (DRG) as well as ongoing activity in the dorsal
horn. The spread of pathophysiology includes upregulation of nitric oxide synthase
(NOS) in axotomized neurons, deafferentation hypersensitivity of spinal neurons following
afferent cell death, long-term potentiation (LTP) of spinal synaptic transmission
and attenuation of central pain inhibitory mechanisms. In particular, the efficacy
of opioids at the spinal level is much decreased following nerve injury. Repeated
or prolonged noxious stimulation and the persistent abnormal input following nerve
injury activate a number of intracellular second messenger systems, implying phosphorylation
by protein kinases, particularly protein kinase C (PKC). Intracellular signal cascades
result in immediate early gene (IEG) induction which is considered as the overture
of a widespread change in protein synthesis, a general basis for nervous system plasticity.
Although these processes of increasing nervous system excitability may be considered
as a strategy to compensate functional deficits following nerve injury, its by-product
is widespread nervous system sensitization resulting in pain and hyperalgesia. An
important sequela of nerve injury and other nervous system diseases such as virus
attack is apoptosis of neurons in the peripheral and central nervous system. Apoptosis
seems to induce neuronal sensitization and loss of inhibitory systems, and these irreversible
processes might be in common to nervous system damage by brain trauma or ischemia
as well as neuropathic pain. The cellular pathobiology including apoptosis suggests
future strategies against neuropathic pain that emphasize preventive aspects.