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COPYRIGHT © 2006 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

Basic Science of Pain

BY JOYCE A. DELEO, PHD
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The origin of the theory that the transmission of pain is through a single channel from the skin to the brain can be
traced to the philosopher and scientist René Descartes. This simplified scheme of the reflex was the beginning of the
development of the modern doctrine of reflexes. Unfortunately, Descartes’ reflex theory directed both the study and
treatment of pain for more than 330 years. It is still described in physiology and neuroscience textbooks as fact
rather than theory. The gate control theory proposed by Melzack and Wall in 1965 rejuvenated the field of pain study
and led to further investigation into the phenomena of spinal sensitization and central nervous system plasticity,
which are the potential pathophysiologic correlates of chronic pain. The processing of pain takes place in an inte-
grated matrix throughout the neuroaxis and occurs on at least three levels—at peripheral, spinal, and supraspinal
sites. Basic strategies of pain control monopolize on this concept of integration by attenuation or blockade of pain
through intervention at the periphery, by activation of inhibitory processes that gate pain at the spinal cord and brain,
and by interference with the perception of pain. This article discusses each level of pain modulation and reviews the
mechanisms of action of opioids and potential new analgesics. A brief description of animal models frames a discus-
sion about recent advances regarding the role of glial cells and central nervous system neuroimmune activation and
innate immunity in the etiology of chronic pain states. Future investigation into the discovery and development of
novel, nonopioid drug therapy may provide needed options for the millions of patients who suffer from chronic pain
syndromes, including syndromes in which the pain originates from peripheral nerve, nerve root, spinal cord, bone,
muscle, and disc.

Pain and Its Treatment:

A Historical Perspective

R
ené Descartes, a philosopher and scientist, can be
credited with the first documented attempt to under-
stand pain. The origin of the theory that the transmis-
sion of pain is through a single channel from the skin to the
brain can be traced to Descartes. This simplified scheme of the
reflex, published in 1664 in the Treatise of Man, was the begin-
ning of the development of the modern doctrine of reflexes1
(Fig. 1). Descartes gives a purely mechanical view of the invol-
untary withdrawal of a foot that comes in contact with a nox-
ious stimulus: “the small rapidly moving particle of fire moves
the skin of the affected spot causing a thin thread to be pulled.
This opens a small valve in the brain and through it animal
spirits are sent down to the muscles which withdraw the foot.
Just as by pulling at one end of a rope one makes to strike at
the same instant a bell which hangs at the other end.” Unfor-
tunately, Descartes’ reflex theory directed both the study and
treatment of pain for more than 330 years. It is still described
in physiology and neuroscience textbooks as fact rather than
theory. This specificity theory proposes that a specific pain
pathway carries the messages from a pain receptor in the skin
to a pain center in the brain, implying that the simple cutting
of this pathway should alleviate all pain. The results of many
clinical cases can confirm that this type of manipulation does Fig. 1
not routinely relieve pain. In fact, damage to nerves can often Line diagram shows the principle of pain transmission as described by
result in exacerbation of painful symptoms, leading to central René Descartes (1596-1650) in Tractatus De Homine (Treatise of Man),
unremitting pain. the definitive French version of which was first published in 1664.
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Fig. 2
Chart shows the main anatomic areas of pain modulation.
Ronald Melzack and Patrick Wall intensely disputed Des-
cartes’ theory. Their gate control theory, proposed in 1965, reju-
venated the field of pain study and led to further investigation
into the phenomena of spinal sensitization and central nervous
system plasticity, which are the potential pathophysiologic cor-
relates of chronic pain2. Later, at a conference in 1995, Wall
commented that the classic picture of a single pain mechanism
is being swept away in favor of a dynamic interlocking series of
biological reactive mechanisms. He said that the model that
purports that a hard-wired, line-labeled, modality-specific, sin-
gle pathway exists that leads from stimulus to sensation is pure
fantasy and that the next few years (in understanding pain) are
going to be revolutionary. The processing of pain takes place in
an integrated matrix throughout the neuroaxis and occurs on at
least three levels—at peripheral, spinal, and supraspinal sites
(Fig. 2). Basic strategies of pain control monopolize on this
concept of integration by attenuation or blockade of pain
through intervention at the periphery, by activation of inhibi-
tory processes that gate pain at the spinal cord and brain, and by
interference with the perception of pain.
Peripheral and Spinal Modulation
of Pain Transmission
t the peripheral level, two distinct populations of afferent
A axons conduct impulses caused by pain or inflammation.
The first group—the myelinated A delta and beta fibers—con-
duct cold and well-localized pain sensations. The second
group—the unmyelinated C fibers—signal pain that is poorly
localized or caused by heat or mechanical stimuli. Tissue dam-
BASIC SCIENCE OF PA I N
age can sensitize these nociceptors, causing the release of alge-
sic mediators such as prostaglandins, potassium, histamine,
leukotrienes, bradykinin, and substance P. This is the rationale
for the use of systemic nonsteroidal anti-inflammatory drugs
and aspirin, which decrease the production of sensitizing
prostaglandins in patients who have acute inflammatory pain.
These fibers synapse in the dorsal horn of the spinal cord,
where spinal modulation occurs (Fig. 2). The gate control the-
ory proposed by Melzack and Wall states that the neural signals
in the dorsal horn from the peripheral input will increase or de-
crease the flow of impulses to higher processing centers in the
central nervous system. The ascending pathways and, in partic-
ular, the spinothalamic tract carry messages to these higher
modulatory centers. Descending inhibitory pathways, which are
mainly noradrenergic and serotonergic modulated, function to
inhibit the release of substance P in the substantia gelatinosa
(lamina II) of the dorsal horn. This is accomplished directly by
the interneurons and/or indirectly by the release of endogenous
opioids. Reynolds3 reported that focal electrical stimulation in
the rat midbrain periaqueductal gray matter allowed surgery
without anesthesia. This led to the concept of descending inhi-
bition as an endogenous system for pain control. Following this
study, Gebhart et al.4 demonstrated that descending input relied
on the medulla, and specifically the rostroventral medulla, in-
cluding the nucleus raphes magnus. In addition, descending fa-
cilitatory pathways have been described extensively as serving to
enhance the gain of pain transmission in the spinal cord5. The
rostroventral medulla also plays a distinct role in producing hy-
peralgesia after peripheral tissue injury by maintaining central
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sensitization through enhancement of the firing of on-cells and
glutamatergic transmission6.
Synaptic transmission between nociceptors and dorsal-
horn neurons is mediated by chemical neurotransmitters re-
leased from central sensory nerve endings. Many neurotrans-
mitter systems have been implicated in this scheme, such as
gamma-aminobutyric acid, adenosine, glycine, and other noci-
ceptive substances (e.g., cholecystokinin-like substances, calci-
tonin gene-related peptide, and glutamate). Under conditions
of persistent injury, C fibers fire repetitively and the response of
dorsal-horn neurons increases. This phenomenon, referred to
as wind-up, is dependent on the release of glutamate, which can
act both at gated N-methyl-D-aspartate receptors and non-N-
methyl-D-aspartate receptors as well as at the glutamate me-
tabotropic receptors. Glutamate also plays a major role in the
process of central sensitization, which produces hyperexcitabil-
ity (reduction in the threshold for action potential firing)
throughout the neuroaxis. Activation of inhibitory processes
that gate pain at the spinal cord can be achieved with the use of
opioids, α2-adrenergic agonists such as clonidine, and tricyclic
antidepressants. Transcutaneous electrical nerve stimulation,
acupuncture, and spinal-cord stimulation have also been pos-
tulated to act by exciting large afferent fibers that decrease
nociceptive activity to inhibit pain responses.
Supraspinal Modulation
of Pain Transmission
he ascending pathways—the spinothalamic, spinoreticular,
T and spinomesencephalic tracts—carry messages to supra-
spinal modulatory centers. Pain can be modulated by electrical
stimulation of specific brain centers. Neurons in several re-
gions of the cerebral cortex (including the somatosensory cor-
tex, thalamus, cingulate gyrus, and the insular cortex) respond
selectively to nociceptive input. How is the cerebral cortex in-
volved in pain processing? The old belief was that the cortex
was the final end in the pathway, and that processing did not
occur here. However, substantial data indicate that this is not
true. In a seminal study, hypnotized volunteers were asked to
immerse a hand in a hot-water bath. The researchers then sug-
gested that the experience was either less unpleasant or more
unpleasant than it actually was. Using positron-emission to-
mography scans, the cingulate cortex was more active when
the volunteer believed that the stimulus was more painful7,
implicating dynamic cortical pain processing.
Although psychological factors rarely cause pain, these
factors may trigger or exacerbate a pain episode, help to main-
tain the pain disorder, and contribute to the distress and disabil-
ity experienced with chronic pain disorders. Treatment plans
should include recognition that modulating pain at peripheral,
spinal, and supraspinal sites may achieve better pain manage-
ment than targeting one site. The three areas of modulation are:
(1) attenuation or blockade of pain through intervention at the
periphery with use of nonsteroidal anti-inflammatory drugs,
regional analgesia, or neural ablative procedures; (2) activation
of inhibitory processes that gate pain at the spinal cord and
brain with use of opioids, α2-adrenergic agonists such as cloni-
BASIC SCIENCE OF PA I N
dine, or tricyclic antidepressants; and (3) the interference with
perception of pain through complementary medicine, psycho-
therapy, hypnosis, relaxation techniques, and biofeedback.
Mechanisms of Action of Morphine
orphine is considered the gold standard of analgesia due
M to its potent action on pain. The specific mechanisms of
action of opioid-induced analgesia, and morphine in particu-
lar, have been extensively investigated. Its action may be due to
effects at spinal and multiple supraspinal sites as well as at po-
tential peripheral sites8. These agents selectively inhibit various
nociceptive reflexes by inhibiting the release of neurotransmit-
ters, including substance P, and mimicking the action of en-
dogenous opioids. Spinal administration of μ-opiates and δ-
opiates produces a potent analgesia in animal models and in
humans at doses that have little effect on other sensory func-
tions. Immunohistochemistry and receptor autoradiography
show that opioid receptors are located on dorsal root ganglion
cells and in laminae I and II of the dorsal horn, suggesting that
these receptors are present presynaptically on C-fiber termi-
nals. Postsynaptically, opioid receptors decrease neuronal excit-
ability by opening potassium channels. Presynaptically, opioids
inhibit neurotransmitter release by inactivating voltage-gated
calcium channels.
Activation of neurokinin-1 receptors in the dorsal horn by
neurokinins (e.g., substance P and neurokinin A) released from
small primary afferent fibers produces neurokinin-1 receptor
internalization in lamina-I neurons9. Therefore, neurokinin-1
receptor internalization indicates substance-P release evoked by
noxious stimuli. Recently, Kondo et al.10 reported that neuroki-
nin-1 receptor internalization evoked by C-fiber stimulation in
spinal-cord slices or by noxious stimulation in vivo was blocked
in a naloxone-reversible manner by agonists of μ-opiate and δ-
opioid receptors delivered spinally. These results indicate that
opioids that are administered intrathecally inhibit noxious
stimuli-induced substance-P release from primary afferent fibers
at doses that were confirmed behaviorally as analgesic.
Potential New Analgesics
he management of chronic pain states remains a major chal-
T lenge. Chronic neuropathic and radicular pain is typically
resistant to opioids and systemic nonsteroidal anti-inflammatory
drugs. Any efficacy attained with these drugs is often offset by
deleterious side effects, including tolerance problems, as in the
case of opioids, thereby limiting the usefulness of these medica-
tions. The cyclooxygenase-2 inhibitors Vioxx (rofecoxib), Cele-
brex (celecoxib), and Bextra (valdecoxib) are newer agents being
used to alleviate both acute and chronic pain. These drugs were
intended to cause fewer gastrointestinal side effects; however,
Vioxx and Bextra were removed from the market after a report
of increased risk of heart attacks and stroke due to loss of the
protective effect of the cyclooxygenase-2 enzyme on the cardio-
vascular system. Therefore, the search for novel targets that can
improve efficacy as well as safety is a major thrust of investiga-
tion by both academia and pharmaceutical companies. For pain
at the peripheral level, the focus has been on several voltage-
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gated channels, including sodium, potassium, and calcium. Al-
though N-type calcium channel blocking medications such as
ziconotide have shown efficacy in refractory chronic pain condi-
tions, side effects remain an issue. Another target is the alpha-2
delta-1 calcium channel subunit, which is the substrate for the
anticonvulsant drug gabapentin. This subunit is important for
channel assembly and is expressed in small dorsal root ganglia
and spinal neurons. Although gabapentin is often used for neu-
ropathic pain, it has limited overall effectiveness and has been as-
sociated with worrisome side effects.
At the spinal level, many targets have been postulated due
to the extensive spinal plasticity associated with both the ini-
tiation and maintenance phases of chronic pain states. These
include cytokine-suppressive anti-inflammatory drugs, local
anesthetic microspheres, combination therapy with novel opi-
oids to decrease tolerance, peptide targets such as neuropeptide
Y, glutamate-calcium blockers, chemokine blockers, and glial
modulating agents.
Applications of Animal Models of Nociception
n understanding of neural mechanisms of both acute and
A chronic pain syndromes has been accelerated by the use
of animal models. These animal models rely on behavioral
end points that provide quantitative assessments of hypersen-
sitivity that are laboratory correlates to human pain. Acute in-
flammatory pain models routinely involve injection of an
irritant into a joint or hind paw. The chronic neuropathic pain
models that have been developed to date involve surgical ma-
nipulation of the sciatic nerve, dorsal root ganglion, or spinal
nerve roots or injury to the spinal cord itself. These models
mostly display numerous common features that have gener-
ated an enormous amount of data culminating in a plethora
of publications. Behavioral testing approaches can be grouped
by the method of stimulation (thermal, chemical, or mechani-
cal) and by the type of stimulus (noxious compared with non-
noxious). The two behavioral tests that are most often used in
chronic pain studies are hyperalgesia (increased sensitivity to a
noxious stimulus) and allodynia (increased sensitivity to a
non-noxious stimulus). Reactions produced by a noxious stim-
ulus can fall into two categories—responses organized by lower
hierarchical areas of the central nervous system, such as with-
drawal reflexes and cardiovascular changes, and more inte-
grated complex responses requiring supraspinal input, such as
tactile hypersensitivity or learned conditioned responses. When
studying any existing or novel animal model, consideration of
the effects of sham surgery are key to the ability to separate
acute pain processing from the desired subacute-persistent be-
havioral hypersensitivity that is being modeled. This is espe-
cially relevant to the development of future animal models of
chronic spinal or disc pain syndromes.
Role of Glia and Neuroimmune
Activation in Chronic Pain States
ecent advancements in the field of pain study have identi-
R fied a central nervous system neuroimmune response that
may act as the driving force for neuronal hypersensitivity, the
BASIC SCIENCE OF PA I N
pathologic correlate to chronic pain following peripheral nerve
injury. Neuroimmune activation involves the activation of non-
neuronal cells such as endothelial and glial cells that, when
stimulated, lead to enhanced production of a host of inflamma-
tory mediators (e.g., cytokines and chemokines). The central
production of proinflammatory cytokines such as interleukin-
1β, interleukin-6, and tumor necrosis factor have been found to
play a key role in the propagation of persistent pain states.
Chemotactic cytokines, or chemokines, also have been recently
identified in the central nervous system neuroimmune cascade
that ensues after injury to a peripheral nerve. The extravasation
of leukocytes from the blood to the site of perceived injury is
defined as the neuroinflammatory aspect of this cascade.
Chemokines directly control this leukocyte transmigration pro-
cess. They are synthesized at the site of injury and establish a
concentration gradient through which immune cells migrate.
Recent studies have demonstrated leukocyte trafficking into the
central nervous system following peripheral nerve or lumbar
nerve-root injury11,12. With use of selective cytokine inhibitors
and neutralizing antibodies as well as glial modulating agents
such as propentofylline, behavioral hypersensitivity has been at-
tenuated in animal models of neuropathy.
In a separate series of studies involving rodent models of
neuropathy, Tanga et al.13 demonstrated a critical role for the in-
nate immunity of the central nervous system by means of the
microglial Toll-like receptor 4 in the induction phase of behav-
ioral hypersensitivity. They hypothesized that after nerve injury,
central nervous system neuroimmune activation and subse-
quent cytokine expression are triggered by the stimulation of
microglial membrane-bound Toll-like receptor 4. To test this
hypothesis, experiments were undertaken to assess tactile and
thermal hypersensitivity in genetically altered mice following
nerve injury. In a complementary study, Toll-like receptor 4 an-
tisense oligodeoxynucleotide was administered intrathecally to
L5 spinal-nerve-injured rats to reduce the expression of spinal
Toll-like receptor 4. Both the genetically altered mice and the
rats treated with Toll-like receptor 4 antisense oligodeoxynucle-
otide displayed significantly (p < 0.05) attenuated behavioral
hypersensitivity and decreased expression of spinal microglial
markers and proinflammatory cytokines compared with their
respective control groups, demonstrating that Toll-like receptor
4 is an initiator of central nervous system neuroimmune activa-
tion following nerve injury. This early, specific, innate central
nervous system-microglial response and the way in which it
leads to sustained glial-neuronal hypersensitivity may point to
new therapies for the prevention and treatment of neuropathic
pain syndromes. Further understanding of the role of non-
neuronal cells, the physiologic mechanisms of central-nervous-
system cytokines and chemokines, and their relevance to neu-
roimmune activation and neuroinflammatory processes may
lead to the development of novel pharmacologic agents for the
treatment and prevention of chronic pain.
Summary
T he integration of pain modulation at multiple foci affords
the clinician an opportunity to address peripheral, spinal,
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and supraspinal mechanisms of pain transmission. By effec-
tively targeting each site, decreased doses of individual agents
may be used to diminish side effects. Synergistic action can
also be expected through this approach. Pain is determined
by an interaction between sensorineural factors and non-
nociceptive factors that comprise both organic and psycho-
logical processes. The enormous explosion of pain research
over the last decade has identified numerous potential targets
for the development of novel analgesics and agents for the pre-
vention and treatment of chronic pain syndromes. The con-
tinuing challenge has been the elusiveness of an efficacious
therapy that is devoid of serious side effects in randomized
controlled clinical trials. The focus on glial modulators and
immune mediator inhibitors may prove advantageous to this
quest and result in superior drug therapy. 
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BASIC SCIENCE OF PA I N
Corresponding author:
Joyce A. DeLeo, PhD
Dartmouth-Hitchcock Medical Center and Dartmouth Medical School,
Neuroscience Center at Dartmouth, Departments of Anesthesiology
and Pharmacology, HB7125, Lebanon, NH 03756. E-mail address:
joyce.a.deleo@dartmouth.edu
The author did not receive grants or outside funding in support of
her research for or preparation of this manuscript. She did not receive
payments or other benefits or a commitment or agreement to provide
such benefits from a commercial entity. No commercial entity paid or
directed, or agreed to pay or direct, any benefits to any research fund,
foundation, educational institution, or other charitable or nonprofit
organization with which the author is affiliated or associated.
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