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in research are clearly in the eye of the beholder,
but what follows is my opinion of some of the major
themes in recent basic science research in pain.
Perhaps not surprisingly, the basis for these themes
is similar to that of other areas of neurobiology
and neuroscience, reflecting the tight integration
and rapid spread of methods and concepts across
laboratory disciplines.
Opioid Drug Action
Clinical use of opioids in the treatment of chronic
pain is controversial due to an unknown risk of
tolerance, addiction and lack of efficacy. Each
of these has a correlate in basic science research.
Basic science studies suggest that opioid tolerance
may reflect traditional mechanisms, such as desensitization
or downregulation in the number of receptors, when
exposed chronically to an agonist. Recent work shows
that these phenomena occur in a nonhomogeneous manner
across the nervous system, perhaps explaining differing
degrees of tolerance to different aspects of opioid
drug action. Receptor desensitization has been shown
to occur rapidly in the spinal cord during chronic
intrathecal drug administration.
Other less traditional mechanisms of tolerance also
are under investigation. For example the reduction
in opioid analgesia with prolonged exposure might
reflect a paradoxical opioid-induced opposing process.
Opioid-induced hyperalgesia occurs after acute and
chronic drug administration in animals, and the
cellular mechanisms in the spinal cord by which
this occurs mimic those responsible for hyperalgesia
from experimental nerve injury.
“[A]lthough we have
focused on descending inhibitory mechanisms to the
spinal cord for decades …
Finally, although we have focused on descending inhibitory
mechanisms to the spinal cord for decades, recent
work suggests that chronic pain may be due in part
to descending facilitatory, pain-enhancing systems.
Some recent evidence suggests that loss of opioid
effect with persistent exposure disappears when these
facilitatory pathways are disrupted.
Peripheral and Central Sensitization
Nerve endings are speculated to become sensitized
in several clinical settings, and recent work has
focused on multiple mechanisms by which peripheral
sensitization occurs. Prostaglandins and catecholamines
sensitize peripheral nerve endings 1) with a time
course far outlasting a brief period of exposure,
2) by different mechanisms in males than females and
3) by interacting with proteins that make up the cell
cytoskeleton. Indeed an emerging area of interest
in neurobiology is the role of cytoskeleton proteins
to divide the cell into compartments, many of which
are specific to how membrane surface receptors produce
their signals.
Another cause of peripheral sensitization and analgesic
drug action involves interaction between resident
or recruited immune cells and peripheral axons or
their support cells. Inflammatory reactions are now
known to occur throughout the length of a nerve after
a focal injury, and immune cell products, including
various cytokines and growth factors, are taken up
by axons and result in local changes in excitability
or transportation to the cell body where they alter
genetic transcription. Areas of recent basic science
in the phenomenon of central sensitization include
release of peripherally transported cytokines to activate
spinal cord glial cells, glial-neuronal interactions
in the spinal cord and activation of descending facilitatory
mechanisms to enhance pain.
Genetic Changes
Initial screens of changes in gene transcription in
the peripheral and central nervous system after injury
leading to neuropathic pain focused on times two to
four weeks after injury. Not surprisingly, in addition
to ion channels and receptor changes, genetic changes
at this time are dominated by inflammatory response
genes. Interestingly, recent work shows that transcriptional
changes which occur several months after injury, in
the face of sustained neuropathic pain behavior, differ
significantly from this early time period. Clinicians
should be aware that the vast majority of recent basic
science discoveries related to mechanisms of neuropathic
pain and new analgesic targets were performed a few
days or weeks after nerve injury, and the contrast
in gene transcription at later time periods than this
questions the relevance of these observations to patients
with longstanding pain.
…
recent work suggests that chronic pain may be due
in part to descending facilitatory, pain-enhancing
systems.”
Ion Channels as Targets for Analgesics
If anything, the focus on ion channels as novel analgesic
targets has increased in recent research. Unlike traditional
analgesics such as opioids, which act on G protein-coupled
receptors, tolerance does not occur to drugs acting
at ion channels for analgesia. Multiple changes in
sodium channel subtypes have been described in several
animal models of pain, and many basic science and
pharmaceutical company laboratories are busy developing
and studying drugs that act specifically at certain
subtypes which change their expression in peripheral
nerves and the spinal cord in pain states. The molecular
site of gabapentin action also is intensely studied,
and recent work in genetically modified mice strongly
suggests that this drug acts to relieve neuropathic
pain by actions on certain types of calcium channels.
Basic science research in pain is rapidly advancing
our understanding of opioid drug action, peripheral
and central mechanisms of sensitization in neuropathic
pain, genetic changes that occur after injury to the
nervous system and lead to pain, and ion channels
as emerging and tempting targets for novel analgesics.
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James C. Eisenach, M.D., is F.M. James III Professor
of Anesthesiology, Center for Study of Pharmacologic
Plasticity in the Presence of Pain, Wake Forest
University School of Medicine, Winston-Salem,
North Carolina. |
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