[ editorial ]

MORTEN HOEGH, PT, MSc, PhD1

Pain Science in Practice (Part 4):

Central Sensitization I

T
his JOSPT Pain Science in Practice article dives into one of consequently, to more activity in WDR
the most important discoveries in contemporary pain-related neurons and/or nociceptive-specific neu-
science: central sensitization. It discusses the different categories rons, which in turn also become sensi-
tized. As the inflammation resolves, the
of synaptic plasticity in the dorsal horn of the spinal cord—
nociceptive stimuli are reduced, WDR/
frequently referred to under the umbrella term central sensitization. nociceptive-specific neurons gradually
This editorial examines the role of glia cells and discusses the clinical return to their “resting state,” and pain
implications of central sensitization. Share your thoughts and and/or hyperalgesia diminishes.4
opinions on central sensitization using and are predominantly transmitted to
#PainScienceInPractice. subcortical areas of the brain via the spi- Secondary Hyperalgesia and Allodynia
Throughout this editorial, central sen- nothalamic tract, mainly via nociceptive- Second-order neurons (WDR/nocicep-
sitization refers to an increase in synaptic specific neurons (neurons that respond to tive-specific) synapse with other neurons
strength as defined by the International high threshold stimuli only). In lamina in the dorsal horn (ie, convergence). This
Association for the Study of Pain: “In- V, input via high threshold receptors (ie, means that primary afferents (eg, C-
creased responsiveness of nociceptive neu- nociceptive stimuli) and low threshold fibers from the skin) with distinctive re-
rons in the central nervous system (CNS) receptors (eg, light touch) are transmit- ceptive fields converge in the dorsal horn.
to their normal or subthreshold afferent ted by wide-dynamic range (WDR) neu- When a primary afferent synapses with,
input.”1 rons. When nociceptive-specific neurons and repeatedly stimulates, a second-or-
or WDR neurons are stimulated repeat- der neuron, synaptic efficacy increases
The Dorsal Horn and Its Neurons edly, they undergo physiological chang- between these 2 neurons, expanding the
The dorsal horn of the spinal cord is ana- es leading to a sensitized state that will receptive fields.7 This is referred to as
tomically divided into laminae (FIGURE 1). outlast the initial stimuli by seconds to homosynaptic plasticity, meaning that
Most nociceptive inputs arrive in lamina hours, or even longer.7 This is referred a specific synapse has been facilitated
I-II (commonly referred to as “superfi- to as activity-dependent central sensi- (FIGURE 2). Expansion of receptive fields
cial laminae” or substantia gelatenosa) tization because it is driven and main- and synaptic facilitation can explain why
tained by neuronal activity (ie, stimuli). stimuli from uninjured skin may lead to
A clinical example involves tissue dam- pain and/or hyperalgesia (ie, secondary
 IASP (International Association for the Study
1

of Pain) terminology can be found here: https://
www.iasp-pain.org/resources/terminology/.
U SYNOPSIS: Central sensitization is an umbrella
term for facilitated synaptic plasticity. This editorial
(1) explains the differences between homosynaptic
and heterosynaptic plasticity, (2) explains the
role of glia cells in dorsal horn neuroplasticity,
and (3) briefly discusses the clinical relevance of
age and subsequent inflammation, which
lead to peripheral sensitization and,
central sensitization and nociplastic pain. Part 5
covers wind-up, classical central sensitization, and
long-term potentiation. J Orthop Sports Phys Ther
2023;53(1):1-4. doi:10.2519/jospt.2023.11569
U KEY WORDS: allodynia, central sensitization,
glia cells, hyperalgesia, pain, synaptic plasticity
hyperalgesia).
Low-threshold stimuli (eg, light touch),
which are mainly transmitted via Aβ-
fibers, can also lead to a pain experience
(ie, allodynia). Heterosynaptic sensiti-
zation might explain why signals from
A-fibers that have not previously been
able to depolarize second-order neurons
in the dorsal horn are now able to do so
(see FIGURE 2). The activity-dependent

1
Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark. ORCID: Hoegh, 0000-0002-9724-767X. No funding was received in
relation to this editorial. Dr Hoegh has received support from nonindustrial, professional, private, and scientific bodies (reimbursement of travel costs and speaker fees) for lectures
on pain, and he receives book royalties from Gyldendal, Munksgaard Denmark, FADL, GAD, and Muusmann publications. Address correspondence to Dr Morten Hoegh, Department
of Health Science and Technology, Faculty of Medicine, Aalborg University, Fredrik Bajers Vej 7D2, 9220 Aalborg, Denmark. E-mail: msh@hst.aau.dk t Copyright ©2023 JOSPT®, Inc

journal of orthopaedic & sports physical therapy | volume 53 | number 1 | january 2023 | 1

 [ editorial ]
to think about the pain experienced after
an acute injury to the skin (FIGURE 3). The
area with damaged skin becomes sensitive
to light touch (allodynia), heat (heat hy-
peralgesia), and pinprick (primary hyper-
algesia). This is likely the consequences of
both peripheral and central sensitization.
Evoked pain around the damaged skin
(allodynia and secondary hyperalgesia)
is closely linked to central sensitization.1
Central sensitization can outlast the
stimuli by hours or days, or even longer;
however, it is essentially considered revers-
ible. Therefore, in the absence of a con-
tinuous trigger (eg, inflammation), central
sensitization would either return to normal
thresholds (homeostasis) or not (ie, become
pathological). Pain can exist in the absence
of injury, with central sensitization consid-
ered a key mechanism. Researchers have
suggested that glia cells could be a missing
link that may explain how central sensitiza-
tion could become (less) reversible.

Glia – Is Half the Story Missing?

The importance of nonneuronal cells in
pain research is now beyond speculative,8
and studying them gives new insights
into the mechanisms of chronic pain.
Studying nonneuronal cells is relatively
new, and it is likely that doing so will pro-
vide novel and important answers in the
future. With regards to central sensitiza-
tion, homosynaptic and heterosynaptic
LTP between C-fibers and nociceptive-
specific neurons depends on activation of
microglia and/or astrocytes10 to varying
extents (see FACT BOX). Therefore, glia cells
could be a missing link in understanding
how nociception can create a “memory
FIGURE 1. Primary afferents with high-threshold receptors (ie, nociceptive neurons) arrive at lamina I, II, and V, trace in nociceptive pathways,” leading to
and action potentials are propagated to higher centers of the central nervous system via nociceptive-specific chronic pain independently of peripheral
and wide-dynamic range (transmission neurons). The schematic shows a C-fiber arriving in lamina I where it
stimuli.10 Even if central sensitization is
synapses with a nociceptive-specific (NS) neuron. Signals from the dorsal horn via the spinothalamic tract arrive
in the thalamus but also connect with areas in the pons. Signals from other sensory organs (eg, vision, sound,
not dependent on glia cells alone, they
and taste) merge in the thalamus, and from here, signals are transmitted throughout the cortex and subcortical are part of a complex interaction at many
regions. levels of the neuroaxis.11

Central Sensitization Is the Tip

heterosynaptic sensitization is referred to Primary and Secondary Hyperalgesia vs of the Iceberg When It Comes to
as classical sensitization, whereas wind-up Peripheral and Central Sensitization Understanding Nociception
and long-term potentiation (LTP) are ho- Understanding the details of central sen- The clinical applications of central sen-
mosynaptic7 (see FACT BOX). sitization is challenging, and it may help sitization are long-debated, often driven

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 FIGURE 3. Hyperalgesia is when a stimulus (eg,
pinprick or heat) that normally provokes pain leads
to pain of greater intensity. Primary hyperalgesia is
FIGURE 2. Schematic illustrating homosynaptic and heterosynaptic plasticity. Homosynaptic refers to increased
characterized as hyperalgesia in an area with injury,
synaptic efficacy (sensitization) of a specific synapse, eg, between a C-fiber activated by electric stimulation and
whereas secondary hyperalgesia is hyperalgesia in
part of a second-order neuron (illustrated as signaling molecules sent from the C-fiber to part of the second-order
an area without injury. Here, primary hyperalgesia
neuron). In contrast, heterosynaptic refers to sensitization between an unstimulated neuron (eg, an Aβ-fiber) and
coincides with the flare, whereas secondary
the second-order neuron (not illustrated).
hyperalgesia is present in uninjured skin.

Fact Box: Glia Cells
Glia cells are resident nonneuronal cells that are
located in the peripheral nervous system and
CNS. Within the CNS, astroglia (or astrocytes) and
microglia are the most studied, but endothelial cells
and T-cells also belong to this category. Astrocytes
influence synaptic transmission (eg, by removing
“unused” neurotransmitters from the synaptic cleft)
and neuronal repair. Astrocytes also make up the
structural part of the blood-brain barrier. Microglia
are sometimes referred to as the CNS counterpart
to macrophages, and they respond to signs of threat
to the CNS (ie, alarmins) by transitioning into a
state in which they can release signaling molecules
to further activate neuronal and nonneuronal cells
(eg, cytokines). See Additional Reading.
by misnomers and speculations such as
whether central sensitization is the cause
of some chronic pain conditions.5 How-
ever, nociception is complex and multiple
mechanisms are likely to coexist and reg-
ulate each other. For example, when LTP
is produced by C-fibers (ie, central sensi-
tization), a “countermeasure” is produced
in the same synapse, which likely controls
or balances the signal-to-noise ratio from
the spinal cord to the rest of the CNS,3
resulting in homeostatic mechanisms
that may prevent or limit central sensiti-
zation. Even if one could treat or reverse
“chronic” central sensitization (and mea-
sure it), it is unclear if or to what extent
treatment could help those experiencing
chronic musculoskeletal pain.2
Nociplastic Pain and
Central Sensitization
How central sensitization relates to the
mechanistic descriptor nociplastic pain
is also a topic of some controversy.6,9 One
problem is that it is impossible to directly
measure central sensitization in humans.
Instead, surrogate measures (typically
temporal summation of pain, second-
ary hyperalgesia, and/or allodynia) are
necessary.13 Although surrogate measures
may be typical, they are not exclusive to
central sensitization.6 In essence, central
sensitization is one of many relevant
and coexisting mechanisms, but pain
is far more complex and still not well
understood.12
Summary: Pain Science in Practice
Repeated stimuli from C-fibers will lead to
changes in the synaptic efficacy in the spi-
nal cord, which have been discussed under
the umbrella term central sensitization.
Such changes outlast the stimuli from the
periphery by seconds to hours, and even
days or months. The scientific discoveries
behind central sensitization are credible
and plausible explanations for why pain
can persist long after an injury has healed
and even in the absence of identifiable pa-
thologies. While central sensitization may
explain pain during and after an injury, it
seems unlikely that it is the (single) cause
of chronic pain. Accordingly, pain reduc-
tion and management of disability related
to chronic pain itself should remain the
clinical goals. Correlates of central sensi-
tization (eg, temporal summation or hy-
peralgesia) at best should be considered
indirect measures of treatment effect. t

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STUDY DETAILS
AUTHOR CONTRIBUTIONS: Dr Hoegh was
responsible for the concept, drafting,
and revisions of the manuscript and is a
guarantor.
DATA SHARING: There are no data in this
manuscript.
PATIENT AND PUBLIC INVOLVEMENT: No pa-
tients or members of the public were
involved in this manuscript.
ACKNOWLEDGMENTS: I would like to acknowl-
edge Dr Mick Thacker for the valuable inspira-
tion and for sparring on the manuscript.
ADDITIONAL READING
Chen G, Zhang Y-Q, Qadri YJ, Serhan CN,
Ji R-R. Microglia in pain: detrimen-
tal and protective roles in pathogen-
esis and resolution of pain. Neuron.
2018;100(6):1292-1311. https://doi.
org/10.1016/j.neuron.2018.11.009
Grace PM, Hutchinson MR, Maier SF,
Watkins LR. Pathological pain and the
neuroimmune interface. Nat Rev Im-
munol. 2014;14(4):217-231. https://
doi.org/10.1038/nri3621
4  |  january 2023  |  volume 53  |  number 1  |  journal of orthopaedic & sports physical therapy
[ editorial ]
Sandkühler J, Gruber-Schoffnegger D.
Hyperalgesia by synaptic long-term po-
tentiation (LTP): an update. Curr Opin
Pharmacol. 2012;12(1):18-27. https://
doi.org/10.1016/j.coph.2011.10.018
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