[ editorial ]

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

Pain Science in Practice: What Is

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-
skeletal rehabilitation. pared to pharmacotherapy.3 Finally, one
Specific and Nonspecific Effects might speculate that active approaches,
From Biomechanics to Neuroscience in Musculoskeletal Pain which enable the patient to self-manage
Historically, most therapists were trained One of the reasons why pharmacotherapy (eg, an active lifestyle), may normalize
to find the (movement) dysfunction and is so central for treating some pathologies endogenous regulation in patients with
to correct it (assuming this would remove is its specificity: The active ingredient in chronic diseases.5
the pain). The proposed linear relation- a drug works directly (as agonist or an- Inflammatory substances (eg, PGE2)
ship between movement and chronic tagonist) or indirectly (via metabolites) act on their specific receptors (see also
musculoskeletal pain does not fit con- on receptors (see below). Similarly, pain Fact Box) to change the function of the
temporary pain science.4,7 Basic research medicine mimics, inhibits, or facilitates neuron. Generally speaking, the sci-
on musculoskeletal pain typically focuses processes related to nociception and pain. entific understanding of chemical and
on understanding the relationship be- Nonsteroidal anti-inflammatory drugs, for thermal transduction is well developed.
tween sensory stimuli (eg, touch or pres- example, inhibit the production of cyclo- Until recently, there was no consensus
sure) and pain, and the most dominant oxygenase (COX) metabolites, including on the understanding of how noxious
field of research is neuroscience, which prostaglandin E2 (PGE2). This molecule mechanical stimuli (eg, intense pres-
is less intuitive for most clinicians than is an agonist for the EP2 receptor, which sure) were transduced. However, now
biomechanics. However, neuroscience plays a pivotal role in sensitization.8 it seems well established that Piezo ion
provides answers to some musculoskel- Nonpharmacological therapies are channels play a pivotal role. How and to
etal pain conundrums, such as how pain likely to target several mechanisms (ie, what degree Piezo ion channels play a
can exist in the absence of pathology and it is unclear exactly how the therapies role in musculoskeletal pain conditions
is still unknown. For the clinician, this
U SYNOPSIS: Biomechanical explanations for
means that the best scientific answer to
cological management of musculoskeletal pain.
musculoskeletal pain are abundant and have been The article also explains the role of different re- the question “Why does it hurt to move?”
used for many years; however, researchers and cli- ceptors and how they relate to clinical conditions. remains to be “sensitization,” ie, activity-
nicians are moving toward neuroscience-based ex- J Orthop Sports Phys Ther 2022;52(4):166-168. or transcription-dependent changes of
planations to study and explain them. This article doi:10.2519/jospt.2022.10994 neurons related to nociception. This is
discusses some specific mechanisms, commonly
U KEY WORDS: musculoskeletal pain, neuroscience,
covered in more detail in a later article,
used in pain medicine, and their somewhat less
specific but equally important role in nonpharma- pain, pain education, pain neurobiology education 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
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-
drophilic molecules. Once the channel
understand how science supplements reactions (ie, signaling pathways). This opens, molecules can cross the mem-
and improves clinical pain manage- means that education, exercise, cognitive brane via the ion channel (and influence
ment, it is essential to understand the behavioral therapy, manual therapy, and the membrane potential). A receptor
“language” of neuroscience. pharmacotherapy may work on the same is a complex unit of proteins that can
Take-home message: Different ther- system and could perhaps be considered identify specific signaling molecules
apies may catalyze the same chemical alternate ways to the same goal. (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

 [ editorial ]
different stimuli (eg, 42°C, local changes receptors function via complex signaling • Dubin AE, Patapoutian A. Nocicep-
in pH, and capsaicin from chili pep- pathways and play an important role in tors: the sensors of the pain pathway.
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ways (see below). Sensory neurons with New York, NY: McGraw-Hill, Health
receptors and ion channels instead of STUDY DETAILS Professions Division; 2021.
sensory organs (eg, Golgi tendon organ) AUTHOR CONTRIBUTIONS: Dr Hoegh was • McMahon SB, Koltzenburg M, Tracey
are commonly referred to as free nerve responsible for the concept, drafting, I, Turk DC. Wall and Melzack’s Text-
endings. Some free nerve endings have and revisions of the manuscript and is book of Pain (6th ed). Philadelphia,
high-threshold receptors (ie, nocicep- guarantor. Pa: Saunders; 2013.
tors; see FIGURE 1), whereas others have DATA SHARING: There are no data in this
low-threshold receptors.6 manuscript.
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168  |  april 2022  |  volume 52  |  number 4  |  journal of orthopaedic & sports physical therapy
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