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26 Chronic Pain: New Molecular Insights into Pain and Treatment
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sensations or what we call ‘phantom pain’. However, cellular and molecular mechanisms contributing to the plastic changes in the neocortex after
amputation remain to be investigated. In addition to the re-organization
ofthe somatosensory cortex, plasticity also occurs in the ACC. In vitro,
inACC slices, synaptic depression induced by low-frequency stimulation
was abolished after the amputation of a single digit in rats. Activation of
various immediate early genes was noted in the ACC, further suggesting
that rapid plastic changes occur within the ACC after amputation [36].
Furthermore, electrophysiological studies in intact animals revealed longterm potentiation of sensory responses in the ACC to noxious hind paw
stimulation after the amputation. Although more studies are needed to
determine signaling molecules contributing to plastic changes, these studies provide strong evidence that long-lasting plastic changes occur in the
ACC after the injury. Our recent data using mutant mice further supported
this possibility. Mice lacking both Ca2+-stimulated adenylate cyclase subtypes 1 and 8 (AC1 and AC8) exhibited reduced allodynia following
inflammation induced by complete Freund’s adjuvant (CFA), while
behavioral responses to acute noxious stimuli were normal. Forskolin
injection into the ACC, which activates the remaining ACs, rescued
thephenotype [37,38]. This suggests that Ca2+-stimulated AC activity in
the ACC participates in the development of hyperalgesia following
amputation [39].
Chronic pain is likely coded in multiple sites
It has become clear that chronic pain is likely coded at multiple sites along
the sensory pathways for pain transmission, modulation, and plasticity
[9,10,24]. The ultimate summary of sensitization in the periphery, spinal
cord, and cortex sites contributes to the enhancement of pain in chronic
pain conditions. It has been reported that inhibiting the plasticity of
AMPA receptors can be analgesic at different levels of the CNS, and it is
still unclear if chronic pain important is mainly stored at synaptic
responses or by the other forms of plasticity, such as changes in action
potentials.
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Glial cells and chronic pain
Microglia are the principal immune-response cells in the CNS. In physiological conditions, they are found in a “resting” state — typically exhibiting ramified processes with high motility. Under pathological conditions,
these cells are transformed from the resting condition to an activated
condition, exhibiting phagocytoxic, chemotaxis, and secretory reactions.
A growing body of literature indicates that spinal microglia can be activated after nerve injury, suggesting the possibility that neuronal activity
may contribute to microglia activation [40,41]. This possibility is further
supported by studies showing that several neurotransmitter receptors can
be expressed on cultured microglia cells, including NMDA, GABA, opioid, and adrenergic receptors. However, in a recent study using the brain
slice preparation for adult mice, we found that microglia did not respond
to either a glutamate or GABA application, or activity-dependent
LTP[42]. In addition to these findings, we found that nerve injury did not
cause any activation of microglial cells in supraspinal central nuclei such
as the ACC where excitatory synaptic transmission was significantly
enhanced after nerve injury. In support of previous reports on the spinal
cord, we also found that microglial cells were activated in the spinal cord
dorsal horn after the nerve injury [43,44]. One possible explanation is that
spinal microglia may be more sensitive to abnormal neuronal activity than
those in higher brain regions.
NR2B: Smart gene for chronic pain treatment
The NMDA receptor is critical for learning-related LTP and behavioral
memory [2]. Genetic overexpression of NMDA receptor 2B (NR2B) (also
called GluN2B) in the forebrains of transgenic mice leads to enhanced
activation of NMDA receptors, facilitating synaptic potentiation in the
hippocampus [45]. These mice also exhibit superior ability in learning and
memory in various behavioral tasks. Memory and pain are often seen as
two distinct physiological functions, however, more and more evidence
suggests that they may also be linked together. In transgenic NR2B mice,
28 Chronic Pain: New Molecular Insights into Pain and Treatment
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enhanced responsiveness to peripheral injection of two inflammatory
stimuli, formalin and complete Freund’s adjuvant (CFA), was found [30].
These results suggest that genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective
agents, may be useful analgesics for persistent pain.
PKMζ: memory kinase to maintain
the pain
Multiple protein kinases are thought to contribute to the induction of LTP
and initial consolidation of information storage. Among them, only protein kinase M zeta (PKMζ) maintains persistent synaptic changes [46]. In
the hippocampus, LTP induction triggers the synthesis of PKMζ, and
activation of PKMζ is critical for late-phase LTP (L-LTP) and memory
consolidation. Interestingly, PKMζ was found to maintain pain-induced
persistent changes in the mouse ACC [47]. Peripheral nerve injury caused
the activation of PKMζ in the ACC, and inhibiting PKMζ by a selective
inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic
potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKMζ in the ACC acts to maintain
neuropathic pain.
Conclusions
In summary, progress in basic neurosciences will continue to affect the
way we study the mechanisms for physiological, pathological, and
chronic pain. Our understanding of pain will improve with the development of new technology and the advancement of our molecular understanding of biological systems. At the systemic level, we are far behind in
our understanding of how brains code sensory information and how consciousness, attention, and emotion are processed, and generated, at the
molecular level. Without this information, we may never be able to understand and ‘cure’ pain.
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Peripheral Nociceptors and
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News and Views
Chapter 2
Sensitization
In the 17th century, philosopher René Descartes described a theory in
which he envisioned threads connecting different parts of the skin with the
brain. In this way, a foot touching an open flame would send a mechanical
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34 Chronic Pain: New Molecular Insights into Pain and Treatment
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Figure 1. Peripheral nociceptors and different fibers. In physiological condition, different sensory inputs are conveyed through various sensory fibers. For example, a gentle
touch is carried out by myelinated afferent fibers, while noxious heat is conducted by small
myelinated (Aδ) and unmyelinated fibers (C). Spinal dorsal horn sensory neurons receive
different sensory inputs, including both non-noxious as well as noxious inputs. That is,
some dorsal horn neurons can respond to a gentle touch as well as noxious heat.
signal to the brain (Figure 1). Discoveries later revealed the existence of
specialized sensory neurons that register changes in our environment.
Joseph Erlanger and Herbert Gasser received the Nobel Prize in
Physiology or Medicine in 1944 for their discovery of different types of
sensory nerve fibers that react to distinct stimuli, for example, in the
responses to painful and non-painful touch. Since then, it has been demonstrated that nerve cells are highly specialized for detecting and transducing differing types of stimuli, allowing a nuanced perception of our
surroundings, including our capacity to feel differences in the texture of
surfaces through our fingertips or our ability to discern both pleasing
warmth and painful heat.
The 2021 Nobel Prize in Physiology or Medicine was awarded jointly
to David Julius and Ardem Patapoutian for their discoveries of receptors
for temperature and touch. David Julius utilized capsaicin, a pungent compound from chili peppers that induces a burning sensation, to identify a
Peripheral Nociceptors and Sensitization 35
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sensor in the nerve endings of the skin that respond to heat. Ardem
Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs.
These breakthrough discoveries launched intense research activities leading to a rapid increase in our understanding of how our nervous system
senses heat, cold, and mechanical stimuli.
Summary
Peripheral noxious stimuli such as heat and cold are converted into neuronal action potentials by nociceptors. Peripheral sensitization of nociceptors is thought to be important for many forms of chronic pain. Abnormal
and ongoing activities from the affected peripheral area trigger and/or
maintain long-term changes in the central nervous system, including the
spinal cord and supraspinal structures. While some forms of chronic pain
may be mainly driven by ongoing activities from peripheral nociceptors,
other forms of chronic pain may be caused by central plasticity induced
by previous peripheral inputs. Thus, investigation of the molecular mechanisms that contribute to peripheral sensitization is important not only for
the understanding of peripheral-dependent chronic pain but also for
understanding how peripheral molecular mechanisms may trigger CNS
plasticity, making chronic pain resistant to any manipulation at the
periphery.
Keywords: DRG; itch; cold; heat; peripheral sensitization; silent
nociceptor; TRPV1; hyperalgesia
Introduction
One major hypothesis for pain transmission is the labeled theory. The
labeled theory proposes that pain information is conducted by selective
proteins and molecules in the central nervous system. Early identification
of nociceptive fibers, and spinal nociceptive neurons, provides strong evidence for selective labeled lines. Recent research into the molecular identification of pain-related receptors provides strong evidence in support of
this theory. However, there is also evidence to the contrary, suggesting that
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