[ editorial ]

MORTEN HOEGH, MSc, PhD, PT, EDPP, RISPT1

Pain Science in Practice: What Is

Pain Neuroscience? Part 1

N
euroscience is a multidisciplinary science that focuses on sory information rather than the input
the nervous system; it forms the backbone of pain research. from vision, hearing, taste, and smell. The
More recently, neuroscience has become a cornerstone of sensory nerve fibers (neurons) are typi-
cally called C, A-delta, and A-beta fibers,
pain management in clinical practice. To help clinicians
but others exist, and to various degrees,
better understand neuroscience, this editorial aims to provide an they can respond to chemical, thermal,
overview of elementary terminology and physiology—providing and mechanical energy. For clinicians,
clinicians with insights into both the usefulness and limitations of it is more important to know that some
neuroscience when it comes to managing model of inducing, testing, and modulat- neurons are activated by gentle stimuli,
musculoskeletal (MSK) pain. ing pain in humans. In other words, while whereas others are only activated by more
Those familiar with the studies of pain pain and nociception are distinct and dif- intense stimuli, due to high-threshold
and nociception will appreciate how diffi- ferent constructs, they have a very intri- receptors (ie, nociceptors). While there is
cult it is to identify and limit the selection cate relationship to each other. In the first a relationship between neuronal activa-
of “key concepts.” Pain is much more than two articles, some fundamental concepts tion and perception (ie, nociception and
neuronal activity; nonetheless, this series will be described to set the scene for the pain), merely activating a sensory nerve
focuses only on the contributions of neu- following articles. fiber does not directly lead to any specific
roscience to our current understanding of perception: Nociceptive stimuli do not
pain. The choices made in the “Pain Sci- Stimuli and Perception equal pain; they activate nociceptors.
ence in Practice” series are supported by If a tree falls in the forest and no one is Good to know about research: Sen-
the European Pain Federation’s curricu- there, does it still make a sound? The fall sory information is obtained from all
lum for pain physiotherapy5 and should will most definitely make particles move types of body tissues (eg, muscles, bones,
cover the topic of “pain mechanisms” re- faster, which can be measured and quan- and tendons). Whereas MSK pain can be
lated to MSK pain conditions. However, tified. However, as sound is a feature of studied using, eg, exercise-induced sore-
the selection is based on contemporary the conscious mind, moving particles will ness, injections, and mechanical pres-
knowledge and may fall short over time. not be perceived as sound unless some- sure, most data from human research
Nociception (i.e., the neural process one is around to hear it. In neuroscience, on nociception originate from studies of
of encoding noxious stimuli) is almost the vibrations (moving particles) are the intact or damaged skin (as opposed to
impossible to measure objectively in the stimulus, and the experience of sound is deep tissues). This is 1 limitation worth
clinic (see FIGURE 1). Yet it is widely accept- the perception. While stimuli should be remembering.
ed that nociception is the most dominant objectively measured or observed, per- Traditionally, nociception (at a cel-
factor in nociceptive pain (e.g., pain dur- ception is subjective. lular/molecular level) has only been
ing inflammation). Within the neurosci- The nervous system detects stimuli, studied in animal models and is either
ences, nociception is likely the most used and here, we shall focus only on the sen- extrapolated to humans or tested in
translational work; however, technologi-
cal advances allow for more studies to be
U SYNOPSIS: This first article in the JOSPT “Pain J Orthop Sports Phys Ther 2022;52(4):163-165.
doi:10.2519/jospt.2022.10995 done in humans or human model systems
Science in Practice” series explains fundamental
and, subsequently, for a more precise un-
concepts related to neuroscience: transduc- U KEY WORDS: neuroscience, pain, pain educa-
tion, transmission, modulation, and perception. tion, pain neurobiology education derstanding of the relationship between
pain and nociception.2,3

1
Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark. No funding was received in relation to this article. 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, 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 Øst, Denmark. E-mail: msh@hst.aau.dk t Copyright ©2022 JOSPT®, Inc

journal of orthopaedic & sports physical therapy | volume 52 | number 4 | april 2022 | 163


FIGURE 1. In some types of experimental pain
research, nociceptive stimuli (eg, pressure, low/high
temperature, or some chemical compounds) are
used to create an experience of pain. This shows how
important nociception is to the experience of pain
and provides important insights into the relationship
between pain and nociception. However, in the
clinic, patients commonly present with nonspecific
pain, and it is the clinician’s job to collect and
organize information from the patient (subjectively
and objectively) and decide if nociception plays a
pivotal role.
FIGURE 2. A schematic with examples of channels and receptors as well as terminology used in the scientific literature.
164  |  april 2022  |  volume 52  |  number 4  |  journal of orthopaedic & sports physical therapy
[ editorial
Transduction, Transmission,
and Modulation
Transduction reflects the change from
1 type of “energy” (ie, chemical, thermal,
and/or mechanical) to another (electric
signals [action potentials]). This is the
basis for the metaphor of “the nervous
system is like an alarm system,” in which
specific, intense stimuli can activate re-
ceptors (see FIGURE 2). Transduction leads
to hyperexcitability through the influx/ef-
flux of ions into the neuron or to “meta-
bolic” changes in the neuron (see part 2
of the series). The adequate stimulus for
nociceptors is 1 or more of the following:
chemical, thermal, and/or mechanical.
When intense stimuli activate nocicep-
tors, the pain experience that usually
follows is known as nociceptive. The 2
other categories are neuropathic and no-
ciplastic,3 which will be covered in later
articles.
A voltage-gated ion channel is an ion
channel that responds to changes in the
membrane potential (see FIGURE 2). If the
net result of transduction is adequate to
]
open the voltage-gated ion channel, lo-
cated along the axon, there will be an ac-
tion potential. The action potential is the
primary component of the transmission
of nociceptive signals. Once the action
potential reaches the central terminal
of the nociceptive neuron in the dorsal
horn of the spinal cord, voltage-gated
ion channels will allow calcium (Ca++)
to flow into the neuron and activate the
process of releasing vesicles (small pack-
ages containing neurotransmitters and
other molecules) into the synaptic cleft.
Neurotransmitters attach to receptors on
the postsynaptic neuron where they may
lead to a new action potential that may be
transmitted via the lateral spinothalamic
tract to the thalamus.
The NaV1.7 is a voltage-gated ion chan-
nel that allows sodium ions to pass
through the membrane of nociceptive
neurons. Groundbreaking research in
humans has identified mutations of the
SCN9A gene that encodes for NaV1.7.
Mutations of NaV1.7 can lead to congeni-
tal insensitivity to pain1 or erythromelalgia,7
establishing a connection between noci-
ception and pain.
In the simple model described above,
one may get the impression that neu-
rons are alone and that only 2 neurons
are involved in the process of transmit-
ting a signal from the periphery to the
thalamus. This is not the case.6 While
transmission occurs in neurons, numer-
ous other cells are involved (eg, glial cells
around the neurons and in the synaptic
cleft). The clinically important message
is that neural transmission relies on com-
plex interactions, which the clinician will
never see or measure.
If the neuron is damaged or com-
promised, the patient may present with
pain (hyperalgesia, allodynia) as well
as increased and/or diminished sensa-
tions (eg, dysesthesia or hypoesthesia).
When the normal, healthy nervous sys-
tem adapts to changes in and around the
body (called modulation), it can lead to
pro- or anti-nociceptive changes, which
are more transient and possibly involved
in many MSK conditions. Modulation,
which includes sensitization phenomena,
is a topic for later in this series.
Part 2 of this series explains how re-
ceptors work and why this relates to our
understanding of MSK pain from a neu-
roscience/mechanism-based model.
Take-home message 1: Nociception is
the neuronal response to intense stimuli,
ie, action potentials in nociceptive neu-
rons. The perception of pain may be the
consequence of nociceptive stimuli, but
pain is subjective and can be experienced
in the absence of nociception. You can try
to rule out nociception in the clinic, but
you can never disqualify the experience of
pain described by a patient.
Take-home message 2: Pay attention
to sensory changes and follow up with a
journal of orthopaedic & sports physical therapy | volume 52 | number 4 | april 2022 | 165
neurological exam.4 Remember, not all
changes are pathological, and modula-
tion of the nervous system is an impor-
tant aspect of its role in survival. t
• Terminology related to pain: https://
STUDY DETAILS
AUTHOR CONTRIBUTIONS: Dr Hoegh was
responsible for the concept, drafting,
and revisions of the manuscript and is
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: The author wants to
thank Prof Mick Thacker for sparring and
support on this manuscript.
SUPPLEMENTAL READING
• Thacker M, Moseley L. Pathophysi-
ological mechanisms of chronic pain.
In: Corns J, ed. The Routledge Hand-
book of Philosophy of Pain. London,
England: Routledge; 2017.
• Kandel ER, Schwartz JH, Jessell TM.
Principles of Neural Science (6th ed).
New York, NY: McGraw-Hill, Health
Professions Division; 2021.
• McMahon SB, Koltzenburg M, Tracey
I, Turk DC. Wall and Melzack’s Text-
book of Pain (6th ed). Philadelphia,
Pa: Saunders; 2013.
• Lewin GR. The evolutionary his­
tory of nerve growth factor and
nociception. Pain. 2020;161:S36-
S47. https://doi.org/10.1097/j.pain.
0000000000001889
• Reichling DB, Levine JD. The primary
afferent nociceptor as pattern generator.
Pain. 1999;82:S103-S109. https://doi.
org/10.1016/S0304-3959(99)00143-8
• Ossipov MH. The perception and
endogenous modulation of pain. Sci-
entifica (Cairo). 2012;2012:561761.
https://doi.org/10.6064/2012/561761
w w w. i a s p - p a i n . o r g /r e s o u r c e s /
terminology/
REFERENCES
1. McDermott LA, Weir GA, Themistocleous
AC, et al. Defining the functional role of
NaV1.7 in human nociception. Neuron.
2019;101:905-919.e8. https://doi.org/10.1016/j.
neuron.2019.01.047
2. Obreja O, Rukwied R, Nagler L, Schmidt M,
Schmelz M, Namer B. Nerve growth factor locally
sensitizes nociceptors in human skin. Pain.
2018;159:416-426. https://doi.org/10.1097/j.
pain.0000000000001108
3. Raja SN, Carr DB, Cohen M, et al. The
revised International Association for the
Study of Pain definition of pain: concepts,
challenges, and compromises. Pain.
2020;161:1976-1982. https://doi.org/10.1097/j.
pain.0000000000001939
4. Schmid AB, Fundaun J, Tampin B.
Entrapment neuropathies: a contempo-
rary approach to pathophysiology, clinical
assessment, and management. Pain Rep.
2020;5:e829. https://doi.org/10.1097/
PR9.0000000000000829
5. Wittink H, Blake C, Doody C, de Groef A, Hoegh
M, Fullen B. Core Curriculum for the European
Diploma in Pain Physiotherapy (EFIC).
European Pain Federation (EFIC); 2017:28.
Available at: https://europeanpainfederation.
org/wp-content/uploads/2018/10/EFIC-Pain-
Physiotherapy-Curriculum1.pdf. Accessed June
20, 2021.
6. Xanthos DN, Sandkühler J. Neurogenic
neuroinflammation: inflammatory CNS reac-
tions in response to neuronal activity. Nat
Rev Neurosci. 2014;15:43-53. https://doi.
org/10.1038/nrn3617
7. Yang Y, Huang J, Mis MA, et al. Nav1.7-A1632G
mutation from a family with inherited erythro-
melalgia: enhanced firing of dorsal root ganglia
neurons evoked by thermal stimuli. J Neurosci.
2016;36:7511-7522. https://doi.org/10.1523/
JNEUROSCI.0462-16.2016
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