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256 Chronic Pain: New Molecular Insights into Pain and Treatment
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stress-induced anxiety may be due to its role in stress-induced CREB
activation, gene expression, as well as long-term depression.
Activity-dependent immediate early genes: cAMP-responsive element
binding protein (CREB) is well-known for its role in activity-dependent
gene regulation and is involved in many neuronal processes, including
synaptic plasticity and memory. Recently, it was found that CREB is also
engaged in emotional behaviors, such as anxiety. CREB knockout mice
exhibited an increase in anxiety-like behaviors in several paradigms,
including the elevated plus maze, light/dark box, and open field. The
mechanism by which CREB is involved in anxiety is not known, but it has
been suggested that CREB could regulate the neuropeptide Y system
(NPY) expression, and decreased concentrations of NPY are implicated in
anxiety-like behaviors.
The zinc finger transcription factor Egr-1 is critical for coupling
extracellular signals to changes in cellular gene expression. Using Egr-1
knockout mice, we have found that it is selectively required for synaptic
potentiation in the amygdala, late auditory fear memory, and anxiety.
Egr-1 knockout mice showed reduced anxiety behaviors as compared with
wild-type mice in the elevated plus maze. The exact mechanism by which
Egr-1 mediates anxiety is currently unknown, but it is likely some downstream gene expression regulated by Egr-1, such as synapsin I and II,
plays a role.
Oxytocin and anxiety
Oxytocin is a well-known neurohypophysial hormone that plays an
important role in behavioral anxiety and nociception. Microinjections of
oxytocin into the ACC attenuate nociceptive responses and anxiety-like
behavioral responses in animals with neuropathic pain [47] (Figure 7).
Application of oxytocin selectively blocks the maintenance of pre-LTP
but not post-LTP. In addition, oxytocin enhances inhibitory transmission
and excites ACC interneurons. Similar results are obtained by using selective optical stimulation of oxytocin-containing projecting terminals in the
ACC in animals with neuropathic pain. These results demonstrate that
oxytocin acts on central synapses and reduces chronic-pain-induced anxiety by reducing pre-LTP.
(a)
(d)
(f)
(b) (c)
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Pain and Anxiety 257
(e)
(g)
(h)
(i)
Figure 7. Microinjected oxytocin into the ACC attenuates chronic pain and anxiety-like
behaviors. (a) Oxytocin (OXT)-immunoreactive (ir) cells in the PVN and projection fibers
in the ACC. (b) and (e) were amplified from white inset on (a) and (d), respectively. The
arrow indicates the expression of exhibits axonal oxytocin-ir in the ACC. No OXT-ir was
observed in the PVN (c) and ACC (f) sections of OXT KO mice. Scale bars: 100 μm in
(a) and (d); 20 μm in (b)–(f). (b) Bilateral microinjection sites for oxytocin in the ACC.
(c) Oxytocin microinjected bilaterally into the ACC significantly increased paw
258 Chronic Pain: New Molecular Insights into Pain and Treatment
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Figure 7. (Continued) withdrawal threshold in nerve injured mice (n = 9 mice/group;
***P < 0.001 for sham versus nerve injury; ###P < 0.001 for saline versus OXT). (d)
Representative traces show the effects on movement of saline/oxytocin in sham/nerve
injured mice in the EPM test. (e) Oxytocin microinjected into the ACC increased the time
spent in open arms, the total number of crossings, and the total travel distance of the EPM
in nerve injury group but had no effect on the sham group (n = 8–11 mice/group; *P < 0.05
and ***P < 0.001 for sham versus nerve injury; #P < 0.05 and ##P < 0.01 for saline versus
OXT). (f) Representative traces show the effects on movement of saline/oxytocin in sham/
nerve injured mice in the open field test. (g) Oxytocin microinjected into the ACC
increased the time spent in the center area, the number of center entries, and the total travel
distance of the open field in the nerve injury group but had no effect on the sham group (n
= 7–8 mice/group; *P < 0.05 for sham versus nerve injury; #P < 0.05 for saline versus
OXT). (h) Microinjected atosiban (peptide antagonist of oxytocin receptor) or L-371,257
(non-peptide antagonist oxytocin receptor) alone had no effect on the pain threshold and
anxiety behaviors in the nerve injured mice (n = 8–12 mice/group; **P < 0.05, **P < 0.01,
and ***P < 0.001 for sham versus nerve injury, unpaired two-tailed t-test). (i) Atosiban or
L-371,257 blocked the analgesic and anxiolytic effects of oxytocin in the nerve injured
mice (n = 8–11 mice/group; **P < 0.01 for sham versus nerve injury, ###P < 0.001 for
saline versus OXT). All error bars denote standard errors (adapted from Li et al. [47]).
Anxiety, descending facilitation, and sensory
disorders
Patients with chronic anxiety and/or depression often complain of a pain
experience that is associated with different parts of the body. The discovery of pre-LTP in the ACC in chronic pain conditions may explain this
heretofore poorly understood clinical phenomenon. Pre-LTP in the ACC
could affect spinal nociceptive transmission through top-down ACC spinal facilitatory systems. Recent studies found that ACC neurons in deeper
layers project to spinal cord dorsal horn neurons [53], and stimulation of
ACC can facilitate nociceptive responses [48]. Such facilitatory effects
may be mediated by descending serotonergic projections from the RVM
[48,49]. Activation of dorsal neurons thus triggers incoming pain-related
somatosensory cortices and produces a pain experience as if it comes from
certain regions of the body. Thus, the ACC-spinal network may provide
the mechanism underlying anxiety-triggered body pain. By activation of
ACC top-down modulation of the dorsal horn, abnormal activity triggered
Pain and Anxiety 259
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by anxiety or fear can initiate neuronal activity in the spinal cord that
interacts with normal ongoing sensory inputs from the periphery. Such
enhancement would then be sufficient to activate pain-related areas in the
cortex, such as the somatosensory cortex, ACC, and insular cortex, triggering the sensation of pain. Some of these activities may further enhance
top-down modulation by positive feedback activity. Thus, this direct cortico-spinal pathway may provide a novel means to link mood changes
with the bodily sensations.
Conclusions
Anxiety is becoming a major medical problem in modern society
[50,51,52]. Humans are suffering from the overload of information, real
or not, which results in the experience of sadness and fear. Their brains are
constantly exposed to all types of somatosensory, visual, and auditory
insults. Altered emotional anxiety levels subsequently affect human decision and thus quality of life. In the case of injury, anxiety can also enhance
the suffering of patients from initial physical injury.
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Chapter 11
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Descending Pain Facilitation
News and Views
New research from a University of Toronto scientist could change the way
we understand pain treatment. Dr. Min Zhuo discovered that the brain’s
frontal lobe is involved in pain transmission to the spine. If his findings in
animals prove to be applicable to humans, this could potentially lead to a
new class of non-addictive painkillers being developed.
For 20 years,Min Zhuo, a professor of physiology in the Faculty of
Medicine at the University of Toronto, has been fascinated by ‘invisible
pain’, in particular chronic invisible pain with no obvious cause. He has
long suspected that the standard way of viewing spinal pain (resulting
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