A joint publication of the Ohio University College of Osteopathic Medicine and the Ohio Osteopathic Foundation
Projection Dorsal root ganglion glutamate, substance P glutamate, Spinal Nerve substance P Spinal Cord Path of DRR excitation from peripheral input
Nociception: NewUnderstandings andTheir Possible Relation toSomatic Dysfunction andIts Treatment
Abstract Efforts to explain the underlying pathophysiology of somatic dysfunction have emphasized the roleof the somatic and autonomic motor systems. Evidence reviewed here indicates that sensory, dorsal root neu-rons may also act in a motor fashion to contribute to peripheral changes that may be involved in somaticdysfunction. The peripheral effects of antidromic activity in sensory nociceptive neurons include neurogenicinflammation and may be triggered from peripheral inputs in a reflex fashion called dorsal root reflexes, orby descending activity from portions of the brain known to be activated by parts of the brain which processemotions. These developments may bring a broader perspective to the understanding of the origin of somaticdysfunction.
Key Words somatic dysfunction, dorsal root reflexes, nociception
Somatic dysfunction (SD) has been a central focus of osteopathic
such sensory modalities as discriminative touch, vibratory sense,
manipulative medicine from its beginnings. Two of the major
theoretical contributions of recent decades regarding somatic
Conversely, small fibers, which arise as naked nerve endings,
dysfunction are those of Korr,1 who emphasized the role of pro-
have delicate sheaths but little or no myelin. As such, they
prioceptors, and of van Buskirk,2 who emphasized the role of
conduct impulses slowly and are involved in warning systems.
nociceptors. In his article, van Buskirk discusses earlier theories
Activation of these small fibers usually requires noxious stimuli,
that emphasized changes of flows of body fluids and changes in
and this event is termed nociception. These fibers are called
connective tissues. As he points out, these flows and changes are
“primary afferent nociceptors,” or PANs. Impulses generated in
undoubtedly involved, but because of the time course of SD and
a PAN are conducted through the spinal nerve back to the dor-
its response to treatment, the search for primary triggers leads
sal horn of the spinal cord. Our perception of nociception often
to the nervous system. More recently Willard has extended the
is that of pain; however, pain is a perception, while nociception
nociceptive model by describing the links between nociception,
is a mechanical event. The two processes can be disassociated.
the neuroendocrine immune system and somatic dysfunction.3
Traditional views have assumed that the neuromuscular
Sensory neurons can act like motor neurons.
changes associated with somatic dysfunction are mediated by
It has long been known that some PAN endings in the skin
altered motor output of the spinal cord via the somatic and
and elsewhere in the periphery can release peptides that cause
sympathetic motor systems. Recent evidence indicates that changes
local responses. In other words, they act in a motor fashion.
in the periphery may also be mediated by signals passing from
This phenomenon is well known as part of the axon reflex, in
the spinal cord to the periphery on sensory neurons.
which, when one branch of a nociceptive afferent in the skin isactivated by a noxious stimulus, action potentials (APs) travel
Organization of the peripheral sensory nervous system.
not only into the spinal cord to register pain, but into the other
The peripheral sensory nervous system is roughly divided into
peripheral branches of the neuron in the skin, where they
two large groups of fibers based on their axon size and function. Large fibers, which arise in encapsulated sensory endings, have
From the Department of Biomedical Sciences, College of Osteopathic
large myelin sheaths and conduct impulses rapidly. Their activity
Medicine, at Ohio University, Athens, Ohio (Dr. Howell), and from the
is conducted to the spinal cord, specifically to the ventral horn
Department of Anatomy, College of Osteopathic Medicine, University of
for reflexes such as the myotatic reflex, and to the large dorsal
New England, Biddeford, Maine (Dr. Willard).
and lateral ascending tracts. Activity in these systems gives us
Address correspondence to Dr. John Howell, Department of Biomedical
Sciences, 211 Irvine Hall, Ohio University, Athens, OH 45701.
HOWELL, WILLARD, Nociception: New Understandings
evidence that stretch receptor sensitivity may be influenced by
antidromically conducted APs on sensory neurons that innervate
these receptors.9 It is possible that vertebrate stretch receptors,
Dorsal root ganglion glutamate,
namely muscle spindles, may prove to be similarly affected,
providing a second means, in addition to the gamma efferent
system, by which the sensitivity to muscle stretch may be varied. glutamate, Spinal Nerve substance P
What mechanism within the spinal cordinitiates motor activity in sensory neurons?
GABA is a transmitter substance that causes depolarization
of the afferent (sensory) nerve endings within the cord. This
Path of DRR excitation from peripheral input
depolarization is called a primary afferent depolarization (PAD). GABAa receptors on these endings are Cl- channels, which
Figure 1. Pathway of the dorsal root reflex. Action potentials are generated peripherally
open in the presence of GABA. When Cl- channels open, the
in one of the two PANs shown and activate fibers of the pain projection pathway and
ending depolarizes. If the depolarization is sufficient to bring
interneurons within the cord. The interneurons, in turn, release GABA onto the endings of
the sensory nerve to threshold, APs are generated and travel
other PANs, causing the primary afferent depolarization (PAD). Low amplitude PADs
antidromically from the spinal cord to the periphery.8
reduce pain sensation by presynaptic inhibition; high amplitude PADs reach threshold to
For a more in-depth explanation of of this process, refer to
excite PANs, triggering action potentials that propagate to the periphery, where they release
substances including substance P and CGRP, which promote neurogenic inflammation.
release substance P and calcitonin gene-related peptide (CGRP).
These substances are responsible for the spread of the wheal of
vasodilation from the site of injury to the surrounding skin, ie,
Evidence suggests that much of the pain and swelling of
for spreading the inflammatory response.
arthritis arises from a positive feedback cycle involving dorsal
What has now become clear is that action potentials can be
root reflexes. In arthritis that has been experimentally induced
generated in the endings of sensory neurons within the spinal
in rats by injection of carageenan into the knee joint, high level
cord through axo-axonal connections. Axons of interneurons
activation of peripheral nociceptors (C-fibers) sends APs into
form synapses on the axons of primary afferents coming in from
the spinal cord. In the cord these impulses activate projection
the periphery.4 Activity of these interneurons may be triggered
fibers which carry that information to the brain. But they also
from other sensory inputs from the periphery5 (Figure 1), or by
activate interneurons that release GABA onto the presynaptic
descending signals from the brain stem6 (Figure 2). Because
endings of these and adjacent C-fibers.5,8
they were first observed in response to the stimulation of other
At low intensities of afferent nociceptive inputs, the low level
peripheral nerves, they were given the name, dorsal root reflexes
release of GABA probably has anti-nociceptive effects, mediated
by presynaptic inhibition. At high levels of nociceptive inputresulting from the carageenan injection, sufficient GABA isreleased to cause suprathreshold depolarizations, which generate
dorsal root reflexes. The effect of antidromic activation of C-
Projection brainstem Dorsal root ganglion
fibers is to release substance P and CGRP in peripheral tissues,
where they enhance the inflammatory response, contributing
to hyperalgesia. This is referred to as neurogenic inflammation. Interruption of this positive feedback cycle by application of
the GABA antagonist, bicuculline, locally within the dorsal
glutamate, substance P
horn of the spinal cord, inhibits efferent activity and reducesknee inflammation (swelling, hyperalgesia, and knee tempera-
ture).8 These experiments indicated that strong nociceptiveinput from the periphery contributes to the inflammatory
Path of DRR excitation from PAG of brainstem
response through this neural circuit.
Central activation of primary afferent depolarization
Action potentials generated in PAN endings within the cord
links emotions and inflammatory processes.
travel to the periphery. The effects they have in the periphery
Dorsal root reflexes can be generated, not only by peripheral
vary. For instance, nociceptive neurons excited centrally release
nociceptive input, but by descending activity from the brain.6,13
substance P, CGRP, and somatostatin in the periphery causing
Electrical stimulation of the midbrain periaquaductal gray (PAG)
neurogenic inflammation.8 Work with invertebrates has provided
in rats elicits depolarization of the endings of primary afferent
nerves in the cord, ie, DRRs. PAG stimulation results in GABA
How does GABA, an inhibitory transmitter, cause excitation in primary afferent
release from interneurons in the cord and serotonin release from
descending fibers originating from the raphe magnus nucleus
First let us consider how GABA causes inhibition, as it does at many
of the brain stem. (PAG gray activity stimulates raphe magnus
synapses. In many cells Cl- is passively distributed, ie, it is not activelytransported across the cell membrane. This explains why the concentration of
activity.) PAG stimulation has been shown to cause pain mod-
chloride is lower inside cells than in the extracellular space. Cl- is repelled from
ulation, in which transmission of nociceptive inputs is inhibited.
the cell by the inside negativity of the cell established by the Na+/K+ pump-
There is evidence that both GABA and serotonin play a role in
leak system. Under these conditions, Cl- is at equilibrium; its equilibrium
this by causing primary afferent depolarization.14 The fact that
potential, calculated from the Nernst equation, is the same as the actual
PAG stimulation affects primary afferent depolarization indi-
membrane potential. Cl- conductance acts to keep the membrane potential ator near its equilibrium potential.10 It acts as a shunt, or short, to attenuate
cates that processes of the central nervous system, which affect
any deviation from resting potential. For instance, increased postsynaptic Cl-
PAG output, have the potential to cause or contribute to neu-
conductance from the inhibitory postsynaptic action of GABA on motor
rogenic inflammation. PAG output is known to be influenced
neurons decreases the amplitude of excitatory postsynaptic potentials occur-
by higher centers – such as the prefrontal cortex and amygdala
ring simultaneously in the cell. The inhibitory action of GABA does not
– areas that are strongly associated with processing emotion.
necessarily involve hyperpolarization; the increased Cl- conductance caused byGABA simply counteracts, or attenuates, the depolarizing effect of excitatory
It is possible that such activity can contribute to localized or
generalized inflammatory disorders, thus providing a neural
Now let us consider how GABA causes excitation. In some cells, such as
link between emotional states and neurogenic inflammation.
primary afferent neurons, Cl- is not passively distributed. In these cells, as inthe cells of the thick ascending limb of the kidney, Cl- is actively transportedinto cells by a Na+/K+/2Cl- transporter, a coupled transporter which drives
Manipulative treatment inhibits pain transmission
Cl- into the cell, driven by the Na+ concentration gradient across the cellmembrane. In this case, the equilibrium potential for Cl- is less negative than
in experimentally-induced joint inflammation.
the resting potential of the cell. When Cl- conductance is increased, Cl- flows
Skyba and colleagues15 have shown that knee joint manipula-
out of the cell, causing depolarization toward the Cl- equilibrium potential.11
tion acts in an analgesic manner in rats with experimentally
This depolarization in primary afferent endings is called the primary afferent
induced arthritis in the ankle joint. This analgesia is blocked
depolarization (PAD). If the PAD reaches threshold, APs are generated and
by local application of a serotonergic blocking agent, methy-
sergide, to the dorsal horn of the cord. Blockade of adrenergic
Is the action of GABA on primary afferents always excitatory?
transmission in the cord with yohimbine (an α2-adrenergic
No. Primary afferent depolarizations which are subthreshold for APs are
blocker) also interferes with the analgesic effect of joint manip-
inhibitory, not excitatory. Subthreshold PADs can actually block the passage
ulation. GABAergic blocking agents had no effect, and neither
of orthodromic APs coming in from the periphery, or at least attenuate their
did the opioid antagonist, naloxone. These results suggest that
amplitudes as they travel into the spinal cord to the nerve endings where they
the analgesic effect of joint manipulation acts at the level of the
cause transmitter release. APs of reduced amplitude reaching nerve endings
brain stem where the descending serotonergic fibers originate.
release less transmitter.11 This mechanism is the basis of presynaptic inhibi-tion. Presynaptic inhibition is common in the nervous system. For instance it
Serotonin, released from neurons descending from the brain stem
is thought to account for the gate-control theory of pain, whereby activation
to the cord, is known to cause PADs. Thus, joint manipulation
of the GABAergic interneurons from stimulation of non-nociceptive
appears to provide analgesia by subthreshold PADs caused by
afferents inhibits transmission from nociceptive neurons to projection neurons
serotonin release. This effect may be a direct effect of serotonin
in the dorsal horn of the spinal cord (accounting for the analgesic action of
released onto primary afferents; serotonin receptors are known
counter-irritants, such as rubbing an injured area or using methylsalicylatepreparations to minimize pain).
to exist on primary afferents in the cord. The effect may also bemediated, at least in part, indirectly by the release of GABA
How does depolarization of the primary afferents, the PAD, prevent or attenuate the
from interneurons, although Skyba’s data suggests that such a
orthodromic transmission of APs to cause pain relief?
mechanism is at best secondary.15 Release of serotonin in the cord
Based on studies of crayfish systems, two possible explanations have been
is also known to activate interneurons which release opioids,
offered.12 One is that the shunting effect of greatly increased Cl- conductance
specifically enkephalin,16 but these appear to play no role in the
decreases AP amplitude so as to decrease transmitter release. The other is that
analgesic effect of manipulation.17 The serotonergic system is
subthreshold depolarizations result in inactivation of Na+ channels. Thedepolarization initially activates some Na+ channels, but not enough to reach
complex, with different receptors that have different, and some-
threshold. These Na+ channels, following activation, quickly inactivate and
times opposite effects on primary afferents.18 Much remains to
are then unavailable to open in response to the orthodromic AP coming in
be learned about this system and its role in pain modulation.
from the periphery. The unavailability of some fraction of the Na+ channels
Further work will be required to elucidate fully the analgesic
means that the inward current associated with the AP is reduced, resulting in
pathways activated by joint manipulation and other forms of
a lower amplitude AP. Another possibility is that APs induced by PADs andtravelling antidromically collide with incoming nociceptive APs, canceling
them out. This raises the question of why APs initiated in the cord by PADsare not perceived as pain. Evidence from the crayfish system indicates that thesite of the axo-axonic synapse is not right at the afferent nerve endings, but at
least 200 µm distant, and that PAD-initiated APs travel only antidromically
Results with the experimental model of arthritis induced in
and do not reach the endings within the cord. The mechanisms by which this
rats by injection of kaolin and carageenan into the knee joint,
occurs are discussed by Cattart and Clarac.12
in which DRR reflexes play a prominent role, suggested thatthe sympathetic nervous system played little or no role.19 DRRs
HOWELL, WILLARD, Nociception: New Understandings
occurred even after sympathectomy or in the presence of
8. Willis WD, Sluka KA, Rees H, Westlund KN. A contribution of dorsal
root reflexes to peripheral inflammation. In: Rudomin P, Romo R, Mendell
LM, eds. Presynaptic Inhibition and Neural Control. Oxford, England: Oxford
The role of sympathetic activity in SD and in the modulation
of pain, however, has been important in osteopathic thinking,20
9. Cattaert D, Bevengut M. Effects of antidromic discharges in crayfish primary
and other experimental evidence has suggested a relation
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between sympathetic activity and somatic dysfunction.21,22 Using
10. Hille B. Ionic Channels of Excitable Membranes. 3rd ed. Sunderland, Mass:
a model of peripheral inflammation induced by injection of
11. Alvarez-Leefmans A, Nani A, Marquez S. Chloride transport, osmotic bal-
capsaicin into the skin of the foot in rats, Lin and colleagues23
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that the enhancement of DRRs caused by induction of the
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In: Rudomin P, Romo R, Mendell LM, eds. Presynaptic Inhibition and
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These results indicate a modulatory role for the sympathetics
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14. Peng YB, Wu J, Willis WD, Kenshalo DR. GABAA and 5-HT3 receptors
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18. Vyklicky L, Knotková-Urbancová H. Primary afferent depolarization and
presynaptic inhibition. In: Rudomin P, Romo R, Mendell LM, eds.
involve primary afferent depolarizations in sensory nerve end-
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primary afferent depolarizations can be nociceptive or anti-
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Much remains to be learned about the behavior of primary
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