[ editorial ]

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

Pain Science in Practice: What Is

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Pain Neuroscience? Part 2

W
e perceive the world through our senses. When the changes work at a molecular level). That does not
in (eg, infection) or around (eg, intense heat) us lead to mean that they are without effect, only
the activation of specific high-threshold receptors, the that the specific effect(s) of a therapy is
unknown.1 Furthermore, nonspecific ef-
nociceptive system protects us. Nociception is an excellent
fects may be as equally effective as potent
pain facilitator, while not the only factor related to the perception of opioids.2 Importantly, the benefits of rec-
pain, and decreasing nociception is generally a highly efficient pain ommended nonpharmacological thera-
reliever of acute pain. This article aims to explain what ion channels pies (eg, education, exercise, and manual
and receptors are and to illustrate their why treatments may work despite being therapy) are many, while also having a
role in the treatment effects for musculo- “nonspecific.” much lower risk of adverse events com-
Copyright © 2022 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

skeletal rehabilitation. pared to pharmacotherapy.3 Finally, one

From Biomechanics to Neuroscience
Historically, most therapists were trained
to find the (movement) dysfunction and
to correct it (assuming this would remove
the pain). The proposed linear relation-
ship between movement and chronic
musculoskeletal pain does not fit con-
Journal of Orthopaedic & Sports Physical Therapy®
Specific and Nonspecific Effects
in Musculoskeletal Pain
One of the reasons why pharmacotherapy
is so central for treating some pathologies
is its specificity: The active ingredient in
a drug works directly (as agonist or an-
tagonist) or indirectly (via metabolites)
on receptors (see below). Similarly, pain
might speculate that active approaches,
which enable the patient to self-manage
(eg, an active lifestyle), may normalize
endogenous regulation in patients with
chronic diseases.5
Inflammatory substances (eg, PGE2)
act on their specific receptors (see also
Fact Box) to change the function of the

temporary pain science.4,7 Basic research
on musculoskeletal pain typically focuses
on understanding the relationship be-
tween sensory stimuli (eg, touch or pres-
sure) and pain, and the most dominant
field of research is neuroscience, which
is less intuitive for most clinicians than
biomechanics. However, neuroscience
provides answers to some musculoskel-
etal pain conundrums, such as how pain
can exist in the absence of pathology and
U SYNOPSIS: Biomechanical explanations for
musculoskeletal pain are abundant and have been
used for many years; however, researchers and cli-
nicians are moving toward neuroscience-based ex-
planations to study and explain them. This article
discusses some specific mechanisms, commonly
used in pain medicine, and their somewhat less
specific but equally important role in nonpharma-
medicine mimics, inhibits, or facilitates
processes related to nociception and pain.
Nonsteroidal anti-inflammatory drugs, for
example, inhibit the production of cyclo-
oxygenase (COX) metabolites, including
prostaglandin E2 (PGE2). This molecule
is an agonist for the EP2 receptor, which
plays a pivotal role in sensitization.8
Nonpharmacological therapies are
likely to target several mechanisms (ie,
it is unclear exactly how the therapies
cological management of musculoskeletal pain.
The article also explains the role of different re-
ceptors and how they relate to clinical conditions.
J Orthop Sports Phys Ther 2022;52(4):166-168.
doi:10.2519/jospt.2022.10994
U KEY WORDS: musculoskeletal pain, neuroscience,
pain, pain education, pain neurobiology education
neuron. Generally speaking, the sci-
entific understanding of chemical and
thermal transduction is well developed.
Until recently, there was no consensus
on the understanding of how noxious
mechanical stimuli (eg, intense pres-
sure) were transduced. However, now
it seems well established that Piezo ion
channels play a pivotal role. How and to
what degree Piezo ion channels play a
role in musculoskeletal pain conditions
is still unknown. For the clinician, this
means that the best scientific answer to
the question “Why does it hurt to move?”
remains to be “sensitization,” ie, activity-
or transcription-dependent changes of
neurons related to nociception. This is
covered in more detail in a later article,
but for now, the message is that pain
is a dynamic process. For clinicians to

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

166 | april 2022 | volume 52 | number 4 | journal of orthopaedic & sports physical therapy
 The aims of parts 1 and 2 in this
Examples of Receptor Types series of articles is to help clinicians
TABLE 1
and Their Agonists a understand the concept of mechanism-
based treatment and why specific and
Agonist Receptor Type nonspecific effects work in parallel and
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Prostaglandin EP2 Metabotropic to share a language that can support the

Substance P NK1 Metabotropic following articles in the series. The next
AMPA, NMDA Ligand-gated receptor article in the “pain science in practice”
Glutamate
mGlu Metabotropic series describes pain mechanisms and
5-HT3 Ligand-gated receptor how modulation relates to clinical pain
Serotonin (5-HT)
5-HT1-2-4-5-6-7 Metabotropic conditions.
GABAA Ligand-gated receptor
GABA
GABAB Metabotropic FACT BOX
𝜇 (mu), 𝛿 (delta), 𝜅 (kappa),
Opioids Metabotropic
Nociceptin/orphanin Understanding Receptors
Nerve growth factor (NGF) TrkA Receptor tyrosine kinase and Ion Channels
Brain-derived neurotrophic factor (BDNF) TrkB Receptor tyrosine kinase An ion channel is a gate-structured
a
This table shows examples of signaling molecules that act as agonists on receptors (ie, activate) found protein that allows passage through
on nociceptive neurons.
the bi-lipid cell membrane layer of hy-
Copyright © 2022 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.

drophilic molecules. Once the channel

understand how science supplements
and improves clinical pain manage-
ment, it is essential to understand the
“language” of neuroscience.
Take-home message: Different ther-
apies may catalyze the same chemical
Journal of Orthopaedic & Sports Physical Therapy®
reactions (ie, signaling pathways). This
means that education, exercise, cognitive
behavioral therapy, manual therapy, and
pharmacotherapy may work on the same
system and could perhaps be considered
alternate ways to the same goal.
opens, molecules can cross the mem-
brane via the ion channel (and influence
the membrane potential). A receptor
is a complex unit of proteins that can
identify specific signaling molecules
(see TABLE 1). Some receptors respond to

FIGURE 1. A schematic with visualization of selected receptors and their agonists. See supplemental reading for more accurate and complete descriptions.

journal of orthopaedic & sports physical therapy | volume 52 | number 4 | april 2022 | 167

different stimuli (eg, 42°C, local changes
in pH, and capsaicin from chili pep-
pers), whereas others are more specific
(eg, PGE2). The most important thing
for the clinician to know about recep-
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tors is that receptors work in different
ways (see below). Sensory neurons with
receptors and ion channels instead of
sensory organs (eg, Golgi tendon organ)
are commonly referred to as free nerve
endings. Some free nerve endings have
high-threshold receptors (ie, nocicep-
tors; see FIGURE 1), whereas others have
low-threshold receptors.6
The ligand-gated receptor works
like a “key in the lock”; a ligand (signal-
ing molecule) attaches to the receptor,
which, in turn, opens an ion channel.
This rapid and highly specific mecha-
Copyright © 2022 Journal of Orthopaedic & Sports Physical Therapy®. All rights reserved.
nism is ideal for subtle adaptations to
minor changes in and around the nerve
cell. The NMDA receptor is an example
of a very important ligand-gated (glu-
tamate) receptor involved in many pro-
cesses and often linked to memory and
wind-up, which will be discussed in a
later article.
Another type of receptor, called metabo-
Journal of Orthopaedic & Sports Physical Therapy®
tropic receptors (or G-protein-coupled
receptors), acts via so-called second mes-
sengers (enzymes and ions) and has the
capacity to rapidly change the function
of the nerve cell (eg, sensitization). They
may work directly on the cell and/or in-
directly via ion channels. The EP2 (pros-
taglandin) receptor, involved in both
peripheral and central sensitization, is
an example.
The third type of receptor, relevant
for clinicians managing pain, is the re-
ceptor tyrosine kinase (Trk receptor),
which modulates functions of the neuron
in response to growth factors such as the
nerve growth factor (NGF) and the brain-
derived neurotrophic factor (BDNF). Trk
168 | april 2022 | volume 52 | number 4 | journal of orthopaedic & sports physical therapy
[ editorial ]
receptors function via complex signaling
pathways and play an important role in
maintaining and adapting the functions
of the nervous system (ie, neuroplasticity)
as well as in the regeneration of damaged
neurons. t
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.Authorship:
ACKNOWLEDGMENTS: The author wants to
thank Prof Mick Thacker for sparring and
support on this manuscript.
SUPPLEMENTAL READING
• Julius D, Basbaum AI. Molecular
mechanisms of nociception. Na-
ture. 2001;413:203-210. https://doi.
org/10.1038/35093019
• Murthy SE, Loud MC, Daou I, et al.
The mechanosensitive ion channel
Piezo2 mediates sensitivity to me-
chanical pain in mice. Sci Transl Med.
2018;10:eaat9897.
• Shin SM, Moehring F, Itson-Zoske
B, et al. Piezo2 mechanosensitive ion
channel is located to sensory neurons
and nonneuronal cells in rat periph-
eral sensory pathway: implications in
pain. Pain. 2021;162:2750-2768.
• Le Pichon CE, Chesler AT. The func-
tional and anatomical dissection of
somatosensory subpopulations using
mouse genetics. Front Neuroanat.
2014;8:21. https://doi.org/10.3389/
fnana.2014.00021
• Dubin AE, Patapoutian A. Nocicep-
tors: the sensors of the pain pathway.
J Clin Invest. 2010;120:3760-3772.
https://doi.org/10.1172/JCI42843
• 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.
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