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276 Chronic Pain: New Molecular Insights into Pain and Treatment
Figure 5. Facilitation of the TF reflex produced by electrical stimulation in the Cg1,
Cg2, and Fr. (a) Brain sites in the ACC for electrical stimulation, illustrated on representative coronal brain sections. Filled circles show sites where electrical stimulation produced
facilitation of the TF reflex. Open circles show sites where electrical stimulation at intensities tested (10–500 µA) produced no facilitation of the TF reflex. Cg1, cingulate cortex,
area 1; Cg2, cingulate cortex, area 2; cg, cingulum; Fr, frontal cortex. Scale bar: 1 mm.
(b)Electrical stimulation delivered to sites within the Cg1, Cg2, or Fr produced significant
decreases in TF response latency. Open bars show TF response latencies measured without
stimulation. Filled bars show TF latencies measured with stimulation. *P<0.05.
(c) Percentage facilitation induced by electrical stimulation in three areas is similar
(adapted from Calejesan et al. [15]).
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activation of metabotropic glutamate receptors (mGluRs) within the ACC
also produced a facilitatory effect. Interestingly, this descending facilitation from the ACC apparently relays on the RVM. In addition, the dorsal
reticular nucleus (DRt) has also been proposed as another possible brainstem relay for descending facilitation from ACC [16]. However, descending facilitation from the DRt on spinal sensory transmission has not yet
been characterized [16].
In addition to the ACC-RVM-spinal pathway, recent studies suggest
that there may be ACC-spinal direct projection in parallel with descending
facilitation modulation. Anatomic studies report that some prefrontal cortical areas, including part of the dorsal ACC, send descending projections
to the spinal cord in rats, monkeys, and mice [17–19]. Electrical stimulation of ACC facilitated excitatory glutamate synaptic transmission in the
spinal cord dorsal horn (Figure 6). This link provides a possible pathway
for ACC neurons to directly regulate the spinal cord neurons. In this study,
in vivo electrophysiological experiments find that activation of ACC
enhances spinal sensory transmission, and this facilitation is independent
of RVM activity.
Optogenetic activation of descending
modulation in vivo
In support of descending facilitation from the ACC in freely moving animals, Kang et al. [20] used optogenetic methods to selectively activate
ACC pyramidal vs inhibitory neurons in mice (Figure 7). They found that
selective activation of pyramidal neurons rapidly and acutely reduced
nociceptive thresholds and that this effect was occluded in animals made
hypersensitive using Freund’s Complete Adjuvant (CFA). Conversely,
inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. These results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation
by PV-expressing interneurons, in nociception [20]. Similarly, it has been
reported that ACC pyramidal cells in the deep layers of the ACC send
direct descending projecting terminals to the dorsal horn of the spinal cord
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Figure 6. ACC stimulation induced facilitation of the sEPSCs on the spinal cord SDH
neurons. (a) A schematic diagram showing the experimental design for ACC electronic
stimulation and in vivo spinal recording. (b, c) One sample (b) and histogram figure
(c) showing ACC stimulation-induced facilitation of the frequency and amplitude of
thesEPSC. (d) Summarized results from 12 SDH neurons. (E) Mapping of the stimulation
sites in the ACC and locations of recorded SDH neurons in the lumbar spinal cord.
*P < 0.05 (adapted from Chen et al. [21]).
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Descending Pain Facilitation 279
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Figure 7. Descending facilitation of behavioral withdrawal by optogenetic activation of
ACC pyramidal cells. (a) Schematic diagram of viral injection site (left) and optic cannula
placement (right) in the ACC. (b) One example of the effects of blue light in a CaMKIIChR2 expressing mouse (red) and an EYFP expressing mouse (black) in the von Frey test.
(c) Pooled data for ChR2 and EYFP mice. On average, there was a reduction in the
mechanical threshold in the ChR2 group. The graph on the right plots the combined data
for the two ON and three OFF episodes. There was a significant effect of laser light in the
ChR2 group but not in the EYFP group. (d) Not all animals showed a decrease in the
mechanical threshold during light activation. Out of 18 animals, 10 showed a decrease
while 8 did not. (e) The overlapped pattern of ChR2 expression in each group. Modified
from Kang et al. (2016) (adapted from Chen et al. [21]).
(laminae I–III). After peripheral nerve injury, these projection cells are
activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs
contribute to the potentiated synaptic transmission of cingulate neurons.
PKA-dependent phosphorylation of GluA1 is important since enhanced
synaptic transmission was abolished in GluA1 phosphorylation site
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serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induces long-term enhancement of cortical-spinal projecting cells in the ACC [14,19,21].
Pathological implications of descending facilitation
It is known that supraspinal neurons are activated by noxious stimuli or
after injury, including those neurons located in the RVM and ACC [22–
24]. Even under physiological conditions, such brief noxious stimuli may
be sufficient to activate descending facilitation from the RVM as well as
the ACC. Facilitated nociceptive transmission at the level of the spinal
cord may assist animals to escape dangerous conditions.
Under pathological conditions, long-term activation of descending
facilitation may contribute to chronic pain, including behavioral allodynia, hyperalgesia, and spontaneous pain after the injury. A positive
feedback mechanism has been proposed to explain how enhanced pain
transmission may directly contribute to the suffering of chronic pain in
patients. Using various animal models, descending facilitation has been
implicated in cancer pain conditions, chronic muscle pain, neuropathic
pain, opioid-induced pain, headache, as well as inflammation-related pain
[25–31]. Especially for the ACC-spinal top-down facilitation, it has been
proposed that it may also contribute to emotional disorders caused by pain
[19,32] (Figure 8).
Conclusions
A better understanding of the molecular and cellular mechanisms for central changes in various pain-related states gives us hope for improved
treatments for chronic pain. At the synaptic level, it is important to understand molecular and cellular mechanisms for long-term plastic changes in
the ACC, RVM, and spinal dorsal horn after peripheral tissue insult. At the
network level, descending facilitation, as well as descending inhibition,
provides a key mechanism to link pain-related neurons located in different
regions of the brain. For facilitation, it will convey the cortical excitation
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Figure 8. Top-down corticospinal network for emotional anxiety-related pain in the
body. Proposed network that may explain anxiety-related somatic discomfort/pain among
patients. Increased ACC activity due to elevated anxiety level trigger descending facilitatory system. Neurons in the deeper layers of the ACC send their axonal projections to
neurons in the RVM of the brainstem that is known to send its modulatory projection to
the spinal cord dorsal horn. Serotonin (5-HT) is the major neurotransmitter for triggering
facilitatory effects on spinal nociceptive transmission. ACC neurons can also project to the
spinal cord dorsal horn directly by corticospinal pathways, and glutamate is the likely
candidate of transmitter. Both facilitatory systems can potentiate spinal excitatory sensory
transmission, and enhance sensory inputs to the brain through spinothalamic pathways.
Consequently, neurons in pain-related cortical regions are activated and contribute to
unpleasantness or discomfort. Depending on the facilitation of sensory inputs from the
region of the body, the activation of neurons in somatosensory cortices then contributes to
the feeling of pain as if it comes from specific parts of the body (adapted from Zhuo [32]).
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back to the level of spinal dorsal horn, a gate region for the entrance of
painful information from the outside. The information on descending
modulation will provide clues for testing new drug targets, for example,
blocking descending facilitatory influences at different levels of the central nervous system (e.g., the ACC and RVM). It is clear that an improved
understanding of endogenous facilitatory systems provides us not only
with the knowledge of the basic physiological mechanisms related to sensory transmission, modulation, and neuron plasticity but also knowledge
that can lead to improved management of persistent and chronic pain
states in patients.
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Chapter 12
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Current Drug and Novel Drug
Target for Treating Chronic Pain
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