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266 Chronic Pain: New Molecular Insights into Pain and Treatment
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from injury or tissue inflammation), and the usual understanding of how
to treat it (block it from entering the spinal cord), wasn’t telling the whole
story. Now, Zhuo has shown, in both mice and rats, that some spinal pain
actually begins in the brain’s frontal lobe — an area previously believed
to be not involved. Zhuo has also demonstrated how treating pain in this
area could be effective in preventing chronic pain.
Zhuo published his results on May 16, 2018, in the journal Nature
Communication. ”When doctors can’t see anything wrong to cause
chronic pain, often they think patients are making it up” says Zhuo, “but
pain that originates in the frontal lobe would be very different from pain
that comes from a physical injury, like a herniated disc. There wouldn’t
necessarily be any injury to ‘see’. That’s because our personality and emotions live in this region. If the frontal lobe can produce physical pain, that
pain would be deeply tied to emotions like anxiety.” Scientists already
knew that the prefrontal cortex was involved in pain in some capacity
because it would light up in scans of people with pain. However, that
activity was always thought to be a symptom — not a cause — says Zhuo.
“When you have extreme anxiety, more neurotransmitters are released
that end up causing pain in the spine,” he says. “Normal functions like
walking shouldn’t be painful. But this flood of neurotransmitters sends the
spine into hyperdrive, and it starts treating ordinary sensations like pain.
That could explain why anxiety can cause chest pain and make you think
you’re having a heart attack. Or why some people experience pain when
you touch them. I believe this helps to explain why emotional pain causes
physical pain.”
The good news is that pain from the frontal lobe seems to be transmitted in a simple, more direct way to the spine making it relatively easy to
shut down. Neurons in the frontal cortex send signals all the way down the
spinal cord, says Zhuo, whereas pain signals from other areas of the brain
are mediated by a complex network.
In animals, Zhuo found that pain was associated with an increase in
neurotransmitters released from the frontal cortex. He was able to lessen
pain by reducing the amount released. His next step is to test this process
in people. For those who suffer from anxiety, along with neuropathic
pain, a painkiller targeting the frontal lobe would be very beneficial, says
Zhuo.
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Summary
It is well known that pain transmission is under modulation of the
descending inhibitory system (or called the endogenous analgesia system). Such inhibitory systems can be tonically active in physiological
conditions. The discovery of descending facilitation in pain transmissions
makes such modulation biphasic. Spinal pathways and spinal transmitters
are different in descending facilitation vs inhibition. While descending
inhibition can be triggered by various supraspinal structures, descending
facilitation is mainly triggered by RVM as well as ACC. Furthermore,
cumulative evidence shows that descending facilitation may become
enhanced in chronic pain conditions.
Keywords: Pain; descending facilitation; ACC; spinal cord; RVM;
descending inhibition; 5-HT
Introduction
Brain activity is able to affect sensory transmission through descending
modulatory systems. For many years, it was believed that endogenous
modulatory systems are mainly inhibitory or ‘analgesic’. Cumulative
studies, however, reveal that descending modulation of spinal sensory
transmission is actually biphasic, including both inhibitory and facilitatory influences. Descending influences from the supraspinal central nuclei
directly, or indirectly, modulates spinal sensory transmission and includes
the ACC, amygdala, PAG, and RVM, which may function as the last relay
between brain centers and the spinal cord [1–4]. Biphasic modulation of
spinal nociceptive transmission from the RVM offers very fine regulation
of spinal sensory thresholds and responses, perhaps reflecting the different types of neurons identified in this area. Integrative approaches have
been used to investigate the mechanisms for descending facilitation,
including electrophysiological, pharmacological, behavioral, and biochemical studies. In this review, we will summarize the data using whole
animal preparations, in vitro spinal and brain slices, and genetically
manipulated mice, to support the hypothesis that the positive feedback
mechanism within the synapses, or between the different brain regions, is
a key mechanism for persistent pain caused by injury.
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Biphasic modulation of spinal pain transmission
The investigation of descending facilitatory systems has been carried out
systematically in the brainstem RVM. At the whole animal level, electrophysiological, pharmacological, and behavioral experiments have been
performed to help characterize the facilitation of responses of spinal sensory neurons to peripheral noxious stimuli, as well as the behavioral
responses to noxious stimuli. Facilitation affects spinal nociceptive transmission from somatocutaneous areas as well as from visceral organs.
Furthermore, facilitation is a common form of modulation of sensory
transmission, affecting both noxious and non-noxious inputs. These
unique features highlight the possibility that descending facilitation may
serve as a key central mechanism that contributes to injury-related central
pain or allodynia.
Biphasic modulation is intensity-dependent
A key feature of descending facilitation is that it is intensity-dependent.
Whether facilitation or inhibition is observed depends, in part, on the
intensity of the stimulation applied (Figures 1 and 2) [4,5]. According to
effects on spinal sensory neuronal responses, we characterize sites within
the brainstem into three different groups: biphasic, inhibitory, and facilitatory sites. At biphasic sites of stimulation, it is typical that electrical
stimulation facilitates spinal nociceptive transmission at lesser intensities
(5–25 µA) and inhibits responses of the same neurons at greater intensities (50–100 µA). At inhibitory sites, electrical stimulation only reduces
and inhibits responses of spinal sensory neurons. At facilitatory sites, we
found that electrical stimulation only caused increases in responses of
spinal sensory neurons. To determine if facilitatory or inhibitory effects
were simply due to different groups of spinal dorsal horn neurons
recorded, we also investigated the effects of electrical stimulation at one
intensity but at different sites in the RVM on the same spinal neuron. We
found that the responses of the same spinal sensory neurons can be either
inhibited or facilitated by electrical stimulation applied to different sites
in the brainstem. Thus, spinal units receive both facilitatory and inhibitory
influences descending from the brainstem. There is no clear anatomical
separation between these different effects produced by stimulation in the
Descending Pain Facilitation 269
(a) (b) (c)
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(d)
Figure 1. Examples (two different spinal neurons) of facilitation (a) and inhibition (b) of
spinal nociceptive mechanical transmission produced by stimulation in the rostral medial
medulla (RMM). (a, b) Peristimulus time histograms (1-s bin width) and corresponding
oscillographic records illustrating a control response to noxious pressure (28.8 g) of the
skin of the hind foot and the effect on responses of the same units during stimulation in
the RMM (intensities given). (c) Graphic representation of the data in a and b; the point
above 0 represents the response (total number of impulses in 10 s) in the absence of RMM
stimulation. (d) Stimulation sites illustrated on a representative coronal brain section
(Paxinos and Watson 1986) and spinal recording sites corresponding to the examples in a
and b. Pyr, pyramidal tract; NGC, n. reticularis gigantocellularis; NGC, NGC pars;
NPGCI, n. reticularis paragigantocellularis lateralis; NRM, n. raphe magnus; VII, facial
nucleus; Sp5, spinal trigeminal tract (adapted from Zhuo and Gebhart [6]).
brainstem. Biphasic effects are often produced at sites of stimulation adjacent to those from which only inhibition is produced by similar intensities
of stimulation. Further to this, inhibitory effects are produced at biphasic
sites of stimulation adjacent to other biphasic sites from which facilitatory
effects are produced. It is unlikely that these effects are simply due to
activation of fibers passing through the RVM because microinjection of
270 Chronic Pain: New Molecular Insights into Pain and Treatment
(a)
(b)
(c)
(d)
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Figure 2. Summary of descending modulation of tail-flick (TF) reflex from the RVM.
(a) TF latency presented as maximum possible inhibition (MPI; inhibitory effect) or %of
control (facilitatory effect) against intensity of electrical stimulation in nucleus raphe magnus (NRM) for inhibitory modulation (○) and biphasic modulation (●). (b, c) Data from
nucleus raphe obscurus (NRO)/nucleus raphe pallidus (NRP) and nucleus reticularis gigantocellularis (NGC)/nucleus reticularis gigantocellularis pars alpha (NGCα) presented as in
A. (d) Sites of stimulation illustrated on representative coronal brain sections (Paxinos and
Watson 1986ꜜ). Pyr, pyramidal tract; Sp5, spinal trigeminal tract; VII, facial nucleus
(adapted from Zhuo and Gebhart [4]).
glutamate or selective receptor agonists into the RVM also produces similar biphasic effects.
Brainstem-spinal cord descending facilitation
For studying the effects of facilitation on stimulation-response functions
(SRFs), responses of spinal neurons to graded, noxious cutaneous, or
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visceral stimuli were studied. In most cases, in particular within the range
of noxious intensities of cutaneous or visceral stimulation, descending
inhibition significantly reduced the slopes of SRFs. In contrast, descending facilitation enabled responses and caused a parallel shift of the SRF to
the left without changing its slope. These different outcomes on the
encoding properties of spinal neurons suggest that descending facilitation
is likely to be mechanistically different from descending inhibition. The
latency to stimulation-produced facilitation and inhibition is determined
by employing a cumulative sum technique and bin-by-bin analysis of unit
responses and further supports the theory that the mechanisms and pathways leading to inhibition and facilitation are different. The mean latency
of stimulation-produced inhibition from the RVM is about 90 ms whereas
the apparent mean latency to facilitation by electrical stimulation is
greater than 200 ms. This suggests that descending facilitatory influences
likely involve sites rostral to the RVM (e.g., ACC, see the following).
Facilitation of nociceptive visceral pain
Spinal visceral pain transmission is also under descending facilitatory
modulation, in addition to the well-known descending inhibitory modulation [2,6,7]. Similar to biphasic modulation of spinal dorsal horn neurons’
responses to cutaneous stimuli, spinal dorsal horn responses to colorectal
distension (CRD) are also biphasic modulated (Figures 3 and 4). Such
descending facilitatory effects can be induced either by electrical stimulation or L-glutamate microinjection into the RVM.
Facilitation of non-nociceptive transmission and
possible implications
WDR neurons respond to both noxious and non-noxious stimuli and are
implicated in the facilitation of ono-noxious responses in chronic pain.
Consistent with these findings, it has been reported that activation of
descending facilitation also increased the responses of spinal dorsal horn
neurons to peripheral non-noxious stimuli, such as non-noxious mechanism brush of the hind paw skin [6]. Such facilitation of dorsal horn neurons’ responses to non-noxious stimuli may contribute to pathological
272 Chronic Pain: New Molecular Insights into Pain and Treatment
(a) (b)
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Figure 3. Example of facilitation of spinal visceral transmission produced by electrical
stimulation and glutamate in the NRM. (a) Peristimulus time histograms (1-s bin width)
and corresponding oscillographic records in the absence (top histograms) and presence
(bottom histograms) of electrical stimulation (25 µA) and glutamate (5 nmoles) given in
the same site in NRM. The intensity and duration of colorectal distension are illustrated
in the following; the period of electrical stimulation (25 s) is indicated by the arrows.
(b)Summary of the data illustrated in A and time course of effect of glutamate given in
NRM. The point above C represents the response to 30-mmHg colorectal distension; the
point above stim represents the response to the same intensity of distension during stimulation in NRM. (c) Site of stimulation and injection of glutamate (adapted from Zhuo and
Gebhart [33]).
(c)
conditions, such as allodynia. Enhanced responses may lead to the activation of cortical areas that receive ascending sensory inputs and thus the
brain may interpret these as noxious stimuli or pain even though the intensity is non-noxious at periphery.
Masked by tonic descending inhibition
Facilitatory influences are observed only at lesser intensities of stimulation (or lesser concentrations of glutamate). In early studies, the presence
(a) (b)
Figure 4. Summary of reproducibility of glutamate-produced facilitation and inhibition.
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(a) Mean peristimulus time histograms (PSTHs; 1-second bin width) representing the
mean visceromotor responses before glutamate administration (unfilled PSTHs) and at 1
minute after glutamate administration (filled PSTHs). The period of distention (20 seconds) is indicated below by the horizontal bar. On the left, mean responses before and after
the first glutamate administration at doses of 5 or 50 nmol are illustrated on top and bottom, respectively. Responses before and after the second glutamate administration at the
same site are illustrated on the right top and bottom, respectively. (b) Graphic illustrations
of the data in A expressed as a percentage of control responses to distention. (c) Summary
of sites where glutamate at a low dose (5 nmol;◯) or greater dose (50 nmol;●) was administered. At 2 sites (◑), both low and high doses of glutamate were tested. (adapted from
Zhuo and Gebhart, [33].
Descending Pain Facilitation 273
(c)
of descending facilitation from the brainstem may have been missed
because brain stimulation intensity-dependent functions were not performed. Descending inhibitory and facilitatory influences are likely to be
simultaneously activated, and prepotent inhibitory effects masked the
facilitatory effects. This idea has been confirmed in experiments investigating spinal pathways for descending modulation. Bilateral transections
of the dorsolateral funiculi (DLFs) in the thoracic spinal cord not only
abolished descending inhibition produced by electrical or chemical stimulation in the RVM but also unmasked descending facilitatory influences
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on spinal sensory neurons at the same high intensities of stimulation that
only produced inhibition before the DLF transactions. These findings suggest that descending inhibitory and facilitatory influences can be simultaneously engaged by activation of sites in the RVM and that removal of the
route conveying the inhibitory influences uncovers descending facilitatory
effects on spinal sensory neurons.
Spinal mechanism for descending facilitation
It is important to show that these modulatory effects are due to changes in
spinal sensory synaptic transmission and not due to modulation of premotor spinal interneurons or spinal local inhibitory synapses. Consistent
with the biphasic modulatory effects of 5-HT on spinal nociceptive transmission and behavioral reflexes, we found that 5-HT produced biphasic
modulation of excitatory synaptic responses in spinal cord slices [8–12]
(see Chapter 4). 5-HT at high doses produces inhibition of AMPA/KA
receptor-mediated excitatory postsynaptic currents (EPSCs), while a low
dose of 5-HT or a selective 5-HT2 receptor agonist induces facilitation of
fast EPSCs in the lumbar spinal cord. 5-HT at low doses could facilitate fast
EPSCs in the presence of an NMDA receptor antagonist, AP-5 (50 µM),
indicating that the facilitatory effect is NMDA receptor-independent.
Application of methysergide after administration of a serotonergic receptor
agonist, DOI, failed to reverse the facilitatory effect of 5-HT. These results
indicate that 5-HT triggers long-term plastic changes in spinal dorsal horn
synapses and continuous activation of 5-HT receptors are not required for
the expression of the facilitation.
5-HT may affect spinal sensory transmission by acting on presynaptic
or postsynaptic receptors. Postsynaptic application of G protein inhibitors,
introduced through the recording pipette, abolished the ability of 5-HT to
facilitate synaptic transmission, suggesting that postsynaptic 5-HT receptors are critical for the effect. In support of this notion, we found postsynaptic Ca2+-dependent processes to be required for 5-HT-induced facilitation.
In experiments with chelating postsynaptic Ca2+ with BAPTA in the
pipette solution, the facilitatory effect of 5-HT was abolished, indicating
that an increase in postsynaptic Ca2+ is required. Additional evidence
against a mechanism of 5-HT-induced synaptic facilitation involving
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modulation of presynaptic glutamate release comes from the observation
that while 5-HT application clearly caused AMPA receptor-mediated
EPSCs, NMDA receptor-mediated EPSCs were significantly decreased by
5-HT in the same neurons. This result suggests that postsynaptic enhancement of AMPA receptor-mediated currents by 5-HT is selective.
Spinal mechanism for descending inhibition
Electrophysiological studies using intracellular or whole-cell patch-clamp
recordings of dorsal horn neurons allow for the investigation of the cellular mechanisms underlying antinociceptive, or analgesic, effects induced
by these transmitters. In anesthetized whole animals, electrical stimulation applied to sites within the nucleus raphe magnus or PAG produced
inhibitory postsynaptic potentials (IPSPs) in dorsal horn neurons including ascending projection spinothalamic tract cells. More detailed pharmacological analyses came from studies using an in vitro brain/spinal cord
slice preparation. In trigeminal nuclei, all three major transmitters, acetylcholine, serotonin, and norepinephrine, are reported to inhibit glutamatergic transmission. In the lumbar spinal cord, less is known about the
synaptic mechanisms underlying sensory inhibition by carbachol, clonidine, and serotonin [13,14].
Facilitation from the cortex
As mentioned above, most investigation of descending facilitation is
focused on subcortical structures, such as the RVM. The possible central
control of RVM-spinal facilitation has been less investigated. One possible structure is the PAG. The PAG-RVM is known to play a key analgesic
effect in descending inhibition of pain. There are a few studies that report
that PAG may exert descending facilitatory effects on spinal transmission.
In addition, it has been known that cortical neurons could project to brainstem neurons and lead to the excitation of descending facilitation [15].
Activation of the ACC at high intensities (up to 500 μA) of electrical
stimulation did not produce any antinociceptive effect. Instead, at most
sites within the ACC, electrical stimulation produced significant facilitation of the TF reflex (i.e., decreases in TF latency) (Figure 5). Chemical
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