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August 1996
Volume 60 |
Number 8
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| Basic Mechanisms
of Pain: Cellular and Molecular Aspects |
Gudarz Davar, M.D.
Pain is a common symptom in a variety of neurologic diseases.
Frequently, pain is due to tissue injury, but in some instances,
damage to peripheral or central somatosensory pathways can result
in persistent pain that is referred to the deafferented regions
of the body surface. For example, in humans, damage to peripheral
nerves can produce persistent pain that is resistant to treatment
with analgesic drugs, including morphine. In animals, damage to
peripheral somatosensory nerves leads to the development of stimulus-evoked
behaviors that suggest that the animal is suffering from experimental
neuropathic pain.
The mechanisms underlying neuropathic pain in humans and the experimental
counterpart in animals are not known in detail, but some of the
determining factors have become evident. These include abnormalities
in the central nervous system such as "central sensitization"
as well as abnormalities in the peripheral nervous system, including
alterations in peripheral target tissue (especially inflammation)
and abnormal excitability of primary afferent neurons (both nociceptors
and low-threshold afferents). This article is focused primarily
on the third of these potential mechanisms.
Behavioral Models
Most current efforts at identifying the primary factors involved
in the generation of neuropathic hyperexcitability have adopted
as a research model somatic nerves innervating the hind limb,
specifically, complete and partial injury to the rat sciatic or
spinal nerves. These injuries are associated with evidence of
stimulus-evoked behaviors that may be indicative of an experimental
painful neuropathy. Such behavioral changes may be the result
of ectopic spontaneous discharges in primary afferents generated
at the injury site or at the level of the dorsal root ganglion.
Spontaneous firing in primary afferents can be generated within
demyelinated portions of injured axons and may be due to structural
alterations of the axon membrane, ectopic autorhythmic firing
or abnormal cross-excitation of high-threshold mechanoreceptors
by activity in large myelinated regenerating afferents.
The mechanisms underlying this hyperexcitability are not known
but could be partially the result of changes in the regulation
of receptors such as adrenoreceptors that are involved in the
modulation of pain transmission in the periphery. Alternately,
primary afferent hyperexcitability that follows injury to somatosensory
nerves in animals could be due to changes in the normal distribution
or expression of transmembrane proteins that serve as regulated
channels for ion flow.
Mechanisms of Hyperexcitability
This article will focus on two families of molecules whose regulation
is expected to be centrally involved in abnormal excitability
in primary afferent neurons. The first involves excitatory modulation
(adrenoreceptors), and the second involves the primary excitability
of the neuron (the voltage-sensitive sodium channel).
Adrenoreceptors: Hyperexcitability in primary afferents
may be the result of changes in the level of expression or distribution
of cell-surface receptors that contribute to the modulation of
excitability in primary afferent neurons. Some classes of alpha-adrenergic
receptors are present on dorsal root ganglion neurons, and indeed,
preliminary data suggest that there may be increases in the surface
density, or upregulation, of alpha2 adrenoreceptors
in primary afferent neurons after partial nerve injury. Alpha-adrenergic
receptors are known to mediate the excitatory effects on injured
sensory neurons of activating postganglionic sympathetic efferents
and hence may be important in understanding sympathetic-related
pain states. Nerve injury triggers massive sprouting of sympathetic
fibers at the injury site. Moreover, it has been found recently
that sympathetic sprouting is also triggered within dorsal root
ganglia after nerve injury. Thus, the substrate for sympathetic-to-sensory
coupling is augmented on both the afferent and the efferent limb.
This pathophysiological coupling may account for the efficacy
of locally or systemically applied alpha-adrenergic antagonists
and of sympatholysis in a subset of patients with nerve injury-associated
pain. It may also partly explain the observation that such pain
is exacerbated by sympathetic efferent activity in some patients,
e.g., micturition-associated pain in amputees.
The Voltage-Sensitive Sodium Channel: The voltage-sensitive
sodium channel is an ion channel essential for electrical excitability
in afferent neurons. Computer simulations show that the threshold
for neuronal firing is highly sensitive to sodium channel density
at the site of impulse initiation (electrogenesis). A small addition
of sodium channels can shift an afferent fiber into a state of
hyperexcitability and even yield spontaneous discharge. It has
been demonstrated recently using channel localization studies
(including immunolocalization) and the sodium channel-specific
ligand, tetrodotoxin, that sodium channels indeed accumulate in
the axon membrane at sites of nerve injury. Moreover, ectopic
hyperexcitability in injured nerves and the neuropathic pain that
accompanies it are transiently suppressed by a range of sodium
channel antagonists. The regulation of sodium channel synthesis
and of membrane insertion are only poorly understood at present.
However, it is known that mRNA for at least one type of sodium
channel gene (brain type III) appears to be upregulated in primary
sensory neurons following peripheral nerve injury in adult rats.
The changes in expression of sodium channels in primary afferents
following constriction injury, and possible correlations with
behavioral hypersensitivity, have just begun to be investigated
and clearly warrant further exploration.
Summary
Evidence of regulated expression of adrenoreceptors or sodium
channels in primary afferent neurons can help establish a potential
role for these molecules in the pathophysiology of experimental
neuropathic pain. Specifically, such changes may permit inferences
to be made about the contribution of these membrane-related activities
to behavioral hyperalgesia and could therefore direct electrophysiologic
and other investigations into the mechanisms of primary afferent
hyperexcitability.
More significantly, if similar findings are identified in humans,
this could lead to the development of better and more selective
drugs, targeted at adrenoreceptors or sodium channels, which could
be used to treat disabling painful neuropathy.
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This article with a complete set of references is available
from the author on request.
Gudarz Davar, M.D., is an Instructor in
Anesthesia (Neuroscience) at Harvard Medical School and Associate
Anesthesiologist at Brigham and Women's Hospital, Boston, Massachusetts.
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