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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 Projection
these receptors.9 It is possible that vertebrate stretch receptors, Dorsal root ganglion
glutamate,
namely muscle spindles, may prove to be similarly affected, substance P
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 Spinal Cord
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 Spinal Nerve
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- Spinal Cord
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 afferents. J Neurophysiol. 2002;88:1753-1765.
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 ance, and presynaptic inhibition. In: Rudomin P, Romo R, Mendell LM, reported that the flare was reduced by previous sympathecto- eds. Presynaptic Inhibition and Neural Control. Oxford, England: Oxford my. Using the same model, Wang and colleagues24 have shown that the enhancement of DRRs caused by induction of the 12. Cattaert D, Clarac F. Presynaptic inhibition in crayfish primary afferents.
In: Rudomin P, Romo R, Mendell LM, eds. Presynaptic Inhibition and inflammation is completely prevented by previous sympathec- Neural Control. Oxford, England: Oxford University Press; 1998:192-205.
tomy or treatment with the α1 adrenergic blocker, terazosin.
13. Proudfit HK, Anderson EG. New long latency bulbospinal evoked potentials These results indicate a modulatory role for the sympathetics blocked by serotonin antagonists. Brain Res. 1974;65:542-546. in neurogenic inflammation, which may vary according to the 14. Peng YB, Wu J, Willis WD, Kenshalo DR. GABAA and 5-HT3 receptors tissue involved or the specific agents causing the inflammation. are involved in dorsal root reflexes: possible role in periaquaductal graydescending inhibition. J Neurophysiol. 2001;86:49-58.
15. Skyba DA, Radhakrishnan R, Rohlwing JJ, Wright A, Sluka KA. Joint manipulation reduces hyperalgesia by activation of monoamine receptors but Direct evidence now exists to support the ideas: (1) that not opioid or GABA receptors in the spinal cord. Pain. 2003;106:159-168.
efferent activity can be initiated on sensory (dorsal root) neurons 16. Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol. 1978;4:451-462.
both from central and peripheral inputs and can travel 17. Vicenzino B, O’Callahan J, Kermode F, Wright A. No influence of naloxone antidromically to generate (neurogenic) inflammation in the on the initial hypoalgesic effect of spinal manual therapy. In: Devor M, periphery; (2) that joint manipulation can reduce hyperalgesia Rowbotham MC, Wiesenfeld-Hallin Z, eds., Proceedings of the 9th World by activating descending serotonergic and adrenergic pain Congress on Pain. Seattle, Wash: IASP Press; 2000:1039-1044.
modulating pathways; and (3) that these two processes both 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- Presynaptic Inhibition and Neural Control, Oxford, England: Oxford Univ.
ings of PANs in the spinal cord. Depending on their intensity, primary afferent depolarizations can be nociceptive or anti- 19. Sluka KA, Lawand NB, Westlund KN. Joint inflammation is reduced by nociceptive, ie, promote pain or inhibit pain. dorsal rhizotomy and not by sympathectomy or spinal cord transaction.
Ann Rheum Dis.1994;53:309-314. Much remains to be learned about the behavior of primary 20. Korr IM. Sustained sympathicotonia as a factor in disease. In: Korr IM, ed.
afferents in response to various inputs, and specifically, their The Neurobiologic Mechanisms in Manipulative Therapy. New York, NY: relation to somatic dysfunction. Osteopathic manipulative tech- niques vary, and simple joint movement, as studied by Sluka 21. Green PG, Jänig W, Levine JD. Negative feedback neuroendocrine control and colleagues19 is no doubt incomplete as a model; but these of the inflammatory response in the rat is dependent on the sympatheticpostganglionic neuron. J Neurosci. 1997;17:3234-3238. results from neuroscience may, nevertheless, point to at least 22. Jänig W, Levine JD, Michaelis M. Interactions of sympathetic and prima- some of the mechanisms through which SD occurs and through ry afferent neurons following nerve injury and tissue trauma. In: which osteopathic manipulative treatment relieves pain and Kumazawa L, Kruger L, Mizumura K. eds. Progress in Brain Research.
Amsterdam, The Netherlands: Elsevier; 1996:161-184. 23. Lin Q, Zhou XJ, Fang L, Willis WD. Sympathetic modulation of acute cutaneous flare induced by intradermal injection of capsaicin in anesthetizedrats. J Neurophysiol. 2003;89:853-861.
1. Korr IM. Proprioceptors and somatic dysfunction. J Am Osteopath Assoc. 24. Wang J, Ren Y, Zou X, Fang L, Willis WD, Lin Q. Sympathetic influence on capsaicin-evoked enhancement of dorsal root reflexes in rats. J Neurophysiol.
2. van Buskirk RL. Nociceptive reflexes and the somatic dysfunction: a model.
J Am Osteopath Assoc. 1990;90:792-809.
3. Willard F. Nociception, the neuroendocrine immune system, and osteopathic medicine. In: Ward RC, executive ed; Hruby RJ, Jerome JA, Jones JM, etal, eds. Foundations for Osteopathic Medicine. 2nd ed. Philadelphia, Pa:Lippincott, Williams & Wilkins; 2003:137-156.
4. Alvarez FJ. Anatomic basis for presynaptic inhibition of primary sensory fibers. In: Rudomin P, Romo R, Mendell LM, eds. Presynaptic Inhibition andNeural Control. Oxford, England: Oxford University Press; 1998:13-49.
5. Cervero F, Laird JMA. Mechanisms of touch-evoked pain (allodynia): a new 6. Peng YB, Kenshalo DR, Gracely RH. Periaquaductal gray-evoked dorsal root reflex is frequency dependent. Brain Res. 2003;976:217-226.
7. Willis WD. Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res. 1999;124:395-421.
A joint publication of the Ohio University College of Osteopathic Medicine

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