Hansen’s Disease Dark Disc Disease Discogenic Back Pain Data Definition Data can be described in one of two of the following ways: i) Pieces of numerical or other information

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D

Daily Persistent Headache

New Daily Persistent Headache

DAMGO

Definition

DAMGO is a μ opioid receptor selective enkephalin derivative: [D-Ala 2 ,N-Me-Phe 4 ,Gly 5-ol]-enkephalin.

Opioids and Inflammatory Pain

Dapsone

Definition

Dapsone is an antibacterial, belonging to a group of sulfonamide-like sulfones. It is used especially in the treatment of leprosy; administered orally.

Hansen’s Disease

Dark Disc Disease

Discogenic Back Pain

Data

Definition

Data can be described in one of two of the following ways:

i) Pieces of numerical or other information.

ii) A set of facts from which conclusions can be drawn.

Postoperative Pain, Data Gathering and Auditing

Data Auditing/Collection/

Gathering/Management/Security

DBS

Deep Brain Stimulation

Deactivation

Definition

Many FMRI experiments show regions of cortex that seem to respond in antiphase with the primary stimulus. This negative BOLD (blood oxygenated level de- pendent) response or deactivation is spatially and tem- porally linked to reductions in blood flow, and has been shown to be primarily due to neuronal inhibition.

Hippocampus and Entorhinal Complex, Functional Imaging

Nociceptor, Fatigue

Dead Sea

Definition

This region in Israel is a major spa area for patients with various types of arthritis.

Spa Treatment

Deafferentation

Definition

Deafferentation means interruption of afferent sensory input due to nerve injury. This may be associated with chronic pain mainly due to mechanisms of peripheral and central sensitization. Although the lesion is usually peripheral, lesions of ascending somatosensory pathways will lead to deafferentation of their target nuclei.

Anesthesia Dolorosa Model, Autotomy

Atypical Facial Pain, Etiology, Pathogenesis and Management

Atypical Odontalgia

Central Nervous System Stimulation for Pain

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528 Deafferentation Pain

Cordotomy Effects on Humans and Animal Models

Dorsal Root Ganglionectomy and Dorsal Rhizotomy

Hyperpathia, Assessment

Peripheral Neuropathic Pain

Plexus Injuries and Deafferentation Pain

Thalamic Plasticity and Chronic Pain

Thalamus, Dynamics of Nociception

Deafferentation Pain

Definition

Neuropathic pain generated in the central nervous system, and secondary to interruption of afferent sensory pathways, projecting onto the concerned central struc- ture. The existence of hyperactive neurons in the deaffer- ented dorsal horn (DH) has been proven by microelec- trode recordings of the DH neurons, in humans as well as in animal experiments. Deafferentation pain may develop after avulsion of the brachial plexus, dorsal root rhizotomy or ganglionectomy, or other types of lesions of peripheral nerves, or because of pathology of the central nervous system.

Brachial Plexus Avulsion and Dorsal Root Entry Zone

Central Pain, Diagnosis

Dietary Variables in Neuropathic Pain

Dorsal Root Ganglionectomy and Dorsal Rhizotomy

Deception

Credibility, Assessment

Decerebrated

Definition

Cerebral brain function (in an animal) and its impact on lower brain and spinal cord can be eliminated experi- mentally by removing the cerebrum, cutting across the brain stem, or severing certain arteries in the brain stem.

Postsynaptic Dorsal Column Projection, Anatomical Organization

Decidualization

Definition

Forming of the deciduas, which is the changed endometrium (the lining of the uterus), after the blasto- cyst (fertilized ovum after 4–9 days of development) is implanted onto the endometrium.

NSAIDs, Adverse Effects

Decision Theory

Statistical Decision Theory Application in Pain As- sessment

Deconditioned

Definition

Deconditioned refers to a state of poor physical conditioning brought on by inactivity.

It is usually used to refer to a deterioration of physical conditioning, secondary to a reduction in an individual’s level of activity. The deconditioning may involve loss of strength, loss of flexibiIity, and reduced cardiovascular function.

Disability, Effect of Physician Communication

Deep Brain Stimulation

N. WEISS, I. GARONZIK, A. SAMDANI, S. OHARA, F. A. LENZ

Johns Hopkins Medical Institutions, Department of Neurosurgery, Baltimore, MD, USA

flenzl@jhmi.edu Synonyms

DBS; Brain electrode Definition

Electrical stimulation of subcortical structures in the brain including peri-ventricular grey;internal capsule

somatic sensory and intralaminar nuclei of thalamus is a therapy for some patients with chronic pain.

Characteristics

Introduction

The electrical stimulation of subcortical brain structures for the treatment of chronic pain was first reported in the 1950s, when hypothalamic nuclei were stimulated for pain control (Tulane University School of Medicine, Dept. of Psychiatry and Neurology 1954;

Pool et al. 1956). Over the next few decades, the sensory

thalamusandperiaqueductal gray(PAG) became the most frequent targets for deep brain stimulation (DBS). This transition followed the observation of stimulation-evoked analgesia, first in animals and sub- sequently in humans (Hosobuchi et al. 1977; Richardson and Akil 1977).

Chronic pain is pain that occurs daily over a 6-month period. Nociceptive refers to pain produced by activa- tion of peripheral nociceptors and transmitted to the central nervous system through intact somatosensory

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Deep Brain Stimulation 529

pathways. Examples of nociceptive pain include pain of acute trauma and cancer pain secondary to inva- sion of bone. This pain responds well to opiates.

Neuropathic painrefers to pain arising from injury to the nervous system either peripherally (deafferentation pain, e.g. diabetic neuropathy) or centrally (central pain, e.g. post-stroke pain) (Portenoy 1989). It has been pro- posed that this type of pain does not respond to opiates (Arner and Meyerson 1988), although this proposal is not universally accepted (Vecht 1989; Dellemijn 1999).

Mechanisms of Action

The mechanisms of action of deep brain stimulation of the PAG and sensory thalamus are not completely understood. Evidence supports the role ofendogenous opioid release in PAG stimulation: focal stimulation of the PAG attenuates nociceptive responses to painful stimuli (Reynolds 1969), an effect that is reversed by opioid antagonists (Hosobuchi et al. 1977), and which is associated with increased endogenous opioid levels in the third ventricle (Akil et al. 1978; Hosobuchi et al.

1979). Several lines of evidence also suggest that the mechanism of analgesia in PAG stimulation involves spinal connections (Basbaum and Fields 1984; Ma- ciewicz and Fields 1986). PAG neurons synapse upon neurons in the medullary nucleus raphe magnus (NRM), which, in turn, sends a strong serotonergic projection to the dorsal horn. This analgesic effect is also abolished by cutting the descending pathways to the spinal cord.

The PAG, medullary NRM and dorsal horn all contain high levels of opiates and opiate receptors. Due to the important role apparently played by opioids, PAG stimulation is usually indicated in chronic nociceptive pain conditions.

The mechanism by which sensory thalamic stimulation provides pain relief is less clearly understood.

The target nucleus for this type of stimulation is the principal somatosensory nucleus, known as ventral caudal (Vc) in humans and ventral posterior (VP) in other species. Stimulation of rat VP inhibits responses to noxious stimulation through an opioid-independent pathway (Benabid et al. 1983). The effects of somatosensory thalamic stimulation on pain modulation may be due to an inhibitory effect on Rexed’s laminae I to Vspinothalamic tract(STT) neurons, most likely through serotonergic pathways (Gerhart et al. 1984).

Due to the relative independence of the opioid pathways, somatosensory thalamic stimulation is indicated in cases of chronic neuropathic pain.

Patient Selection

The issue of patient selection for placement of DBS for the treatment of pain has been addressed in a number of published studies (Young and Rinaldi 1997; Levy et al. 1987; Hosobuchi 1986). These patients experienced chronic pain, unresponsive to medical or surgical ther- apies over several years, and failed treatment adminis-

tered during an admission to a pain clinic. Often, they underwent psychosocial assessment, and were selected for stimulation if there is no evidence of psychological or secondary gain issues. In many published studies, patients have been subjected to intravenous morphine infusion tests, based on the hypothesis that nociceptive but not neuropathic pain responds to opioids. Reversibility of analgesia with naloxone is taken as further evidence of a nociceptive pain condition. If the patient’s pain was likely to be nociceptive in origin, PAG stimulation was performed. If the pain appeared to be neuropathic, the patient underwent thalamic stimulation.

Intraoperative Targets

Localization of the surgical target for PAG has been determined using different means by different authors.

All targets were determined relative to the anterior commissure-posterior commissure (AC-PC) line, a third ventricular radiologic landmark with a relatively fixed anatomic relationship to subcortical structures.

Levy and co-workers targeted a point 1 mm below and 1 mm posterior to the posterior commissure, and 3 mm lateral to the lateral wall of the third ventricle (Levy et al. 1987). Young and Rinaldi targeted a point 2 to 3 mm below the AC-PC line, 12 to 14 mm posterior to the midpoint (MC) of the AC-PC line and 2 to 3 mm lateral to the midline (Young and Rinaldi 1997).

Hosobuchi targeted a site at the level of the opening of the aqueduct into the third ventricle and 3 mm lateral to the midline (Hosobuchi 1986). The correct target was identified by stimulation-evoked warmth, oscillopsia, loss of up-gaze, elevation of both heart rate and blood pressure, or pain relief. If the electrode is implanted more ventrally and posterior – in periaquaductal grey, fear and anxiety are evoked by stimulation (Hosobuchi 1986). Periventricular gray, which is slightly rostral to PAG, has been targeted as an alternative site to PAG in some studies. The periventricular gray is located 10 mm posterior to MC, at the vertical level of the AC-PC line, and 3 to 4 mm lateral to the midline (Young and Rinaldi 1997).

Levy and co-workers described sites of thalamic targets for treatment of deafferentation pain (Young and Rinaldi 1997). Targets for facial deafferentation pain in the me- dial Vc (facial representation of Vc) were chosen 8 mm posterior to the MC point, 8 mm lateral to the midline, and 1 to 3 mm above the MC point. Deafferentation pain of the extremities was treated by stimulation of lateral Vc (representation of the extremities), defined as a point 9 mm posterior to MC, 10 to 12 mm lateral, and 2 to 3 mm above the MC point. In other studies, targets were calcu- lated from standard atlas maps. All studies included a period of postoperative testing with the electrode attached to an externalized lead. Patients were stimulated at different electrode combinations, voltages, pulse widths, and frequencies until the optimal stimulation parameters for pain relief were determined. The results of this period

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530 Deep Brain Stimulation

of postoperative testing were used to decide whether to implant the stimulator permanently.

Results

Three large studies have reported the results of deep brain stimulation for the treatment of pain. Young et al.

retrospectively reviewed 178 patients over 14 years who had DBS for chronic pain (Young and Rinaldi 1997).

Early in their experience, they relied on screening tests, such as response of pain to opiates and reversal of pain relief with naloxone, to determine the surgical target of DBS. Later in their experience, electrodes were implanted in both PAG and Vc in most patients, and the ideal stimulation parameters were determined through post-operative DBS programming. Of the 89 patients with permanent implants, 62% experienced long-term pain relief. Long-term pain relief was obtained in 70%

of patients with nociceptive pain, and in 50% of patients with neuropathic pain.

Another study reported the results of DBS for chronic pain in 161 patients over 80 months. Patients given pain relief with morphine infusion and reversal with naloxone had PAG stimulation, those who had no response had Vc stimulation, and those with a mixed response had electrodes placed in both locations. Success was measured by regular use of the electrode at initial (6 weeks) and long term (>6 weeks) follow-up. Overall, there was a 61% initial success rate and a 30% long-term success rate. Patients with nociceptive pain had a 56% initial success rate and a 32% long-term success rate, while patients with neuropathic pain experienced 20–50% success rates (Levy et al. 1987). In a third study, 122 patients had thalamic DBS placed for chronic pain, with 68% initial and 57% long-term success rates (Hosobuchi 1986).

A meta-analysis of 13 studies (1114 patients) evaluat- ing DBS for the treatment of chronic pain reported that 50% of all patients experienced long term pain relief.

Patients with nociceptive pain experienced a 60% long- term relief of pain with PAG stimulation. Patients with neuropathic pain experienced a 56% long-term success rate with Vc stimulation.

Complications

Hemorrhage is the most serious complication of DBS, occurring in 14/441 cases and leading to 3 deaths. This has been attributed to the design of the electrode, which has since been modified (Levy et al. 1987; Hosobuchi 1986; Young and Rinaldi 1997). Neurologic sequelae of stimulation were reported in 7% of cases, including diplopia, vertical gaze paresis, blurred vision, oscillopsia, hemineglect and hemiparesis. In one study, persistent headache occurred in 50% of cases; however, this was not mentioned in others (Young and Rinaldi 1997).

Infections occurred in 5–12% of cases (Young and Rinaldi 1997; Levy et al. 1987; Hosobuchi 1986), with staphylococcus species being the majority of causative organisms. Stitch and subgaleal infections were most

common, and were usually treated adequately with antibiotics. Removal of the hardware system and intravenous antibiotics were successful in treating the hardware infections. Ventriculitis (Propionobacterium) and subdural empyema (Staphylococcus aureus) rarely occurred.

Technical failures were reported in all studies, including electrode migration (2–10%) and insulation fracture (3–4%). Skin erosion was reported in 2% of cases. The technical complication rate has decreased with the newly designed electrode.

Pain Treatment, Motor Cortex Stimulation

Postherpetic Neuralgia, Pharmacological and Non- Pharmacological Treatment Options

Stimulation Treatments of Central Pain

References

1. Akil H, Richardson DE, Hughes J, Barchas JD (1978) Enkephalin-Like Material Elevated in Ventricular Cerebrospinal Fluid of Pain Patients after Analgetic Focal Stimulation. Science 201:463–465

2. Arner S, Meyerson BA (1988) Lack of Analgesic Effect of Opi- oids on Neuropathic and Idiopathic Forms of Pain. Pain 33:11–23 3. Basbaum AI, Fields HL (1984) Endogenous Pain Control Sys- tems: Brainstem Spinal Pathways and Endorphin Circuitry. Ann Rev Neurosci 7:309–338

4. Benabid AL, Henriksen SJ, McGinty JF, Bloom FE (1983) Thala- mic Nucleus Ventro-Postero-Lateralis Inhibits Nucleus Parafas- cicularis Response to Noxious Stimuli through a Non-Opioid Pathway. Brain Res 280:217–231

5. Dellemijn P (1999) Are Opioids Effective in Relieving Neuro- pathic Pain? Pain 80:453–462

6. Gerhart KD, Yezierski RP, Wilcox TK, Willis WD (1984) Inhi- bition of Primate Spinothalamic Tract Neurons by Stimulation in Periaqueductal Gray or Adjacent Midbrain Reticular Formation.

J Neurophysiol 51:450–466

7. Hosobuchi Y, Adams JE, Linchitz R (1977) Pain Relief by Elec- trical Stimulation of the Central Gray Matter in Humans and its Reversal by Naloxone. Science 197:183–186

8. Hosobuchi Y, Rossier J, Bloom FE, Guillemin R (1979) Stimu- lation of Human Periaqueductal Gray for Pain Relief Increases Immunoreactive Beta-Endorphin in Ventricular Fluid. Science 203:279–281

9. Hosobuchi Y (1986) Subcortical Electrical Stimulation for Con- trol of Intractable Pain in Humans. Report of 122 cases (1970- 1984). J Neurosurg 64:543–553

10. Lenz FA, Kwan HC, Martin R, Tasker RR, Richardson RT, Dostrovsky JO (1994) Characteristics of somatotopic organization and spontaneous neuronal activity in the region of the human principal sensory nucleus in patients with spinal cord transection. J Neurophysiol 72:1570-1587

11. Lenz FA, Zirh AT, Garonzik IM, Dougherty PM (1998) Neuronal Activity in the Region of the Principle Sensory Nucleus of Human Thalamus (Ventralis Caudalis) in Patients with Pain Following Amputations. Neuroscience 86:1065–1081

12. Levy RM, Lamb S, Adams JE (1987) Treatment of Chronic Pain by Deep Brain Stimulation: Long Term Follow-up and Review of the Literature. Neurosurgery 21:885–893

13. Maciewicz R, Fields HL (1986) Pain pathways. In: Asbury AK, McKhann GM, McDonald WI (eds) Diseases of the Nervous Sys- tem. Clinical Neurobiology. W.B. Saunders Company, Philadel- phia, London, pp 930–940

14. Pool JL, Clark WK, Hudson P, Lombardo M (1956) Hypothalamic- Hypophysial Dysfunction in Man. Laboratory and Clinical Assessment. In: Guillemin R, Guillemin R, Carton CA (eds) Hypothalamic-Hypophysial Interrelationships. Thomas, Spring- field, pp 114–124

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Degenerative Joint Disease 531

15. Boivie J (1994) Central pain. In: Wall PD, Melzack R (eds) Text- book of Pain. Churchill Livingston, Edinburgh, pp 87^1-902 16. Radhakrishnan V, Tsoukatos J, Davis KD, Tasker RR, Lozano

AM, Dostrovsky JO (1999) A Comparison of the Burst Activity of Lateral Thalamic Neurons in Chronic Pain and Non-Pain Patients.

Pain 80:567–575

17. Reynolds DV (1969) Surgery in the Rat During Electrical Anal- gesia Induced by Focal Brain Stimulation. Science 164:444–445 18. Richardson DE, Akil H (1977) Pain Reduction by Electrical Brain Stimulation in Man: Part II: Chronic Self Administration in the Periaqueductal Gray Matter. J Neurosurg 47:184–194 19. Tulane University, School of Medicine.Dept.of Psychiatry

and Neurology (1954) Studies in Schizophrenia. A Multi- disciplinary Approach to Mind-Brain Relationships. Harvard University Press, Cambridge

20. Turk DC, Okifuji A (2001) Pain Terms and Taxonomies of Pain.

In: Loeser JD (ed) Bonica’s Management of Pain. Lippincott Williams & Wilkins, Philadelphia, Baltimore, New York, Lon- don, Buenos Aires, Hong Kong, Sydney, Tokyo, pp 17–25 21. Vecht ChJ (1989) Nociceptive Nerve Pain and Neuropathic Pain.

Pain 39:243–244

22. Young RF, Rinaldi PC (1997) Brain stimulation. In: North RB, Levy RM (eds) Neurosurgical management of pain. Springer- Verlag, New York, Berlin, Heidelberg, pp 283–301

Deep Dysparuenia

Definition

Lower abdominal pain exclusively during intercourse.

Gynecological Pain and Sexual Functioning

Deep Sedation

Definition

A drug-induced state of depressed consciousness during which patients are not easily aroused and may need air- way and ventilatory assistance, although they purpose- fully respond to repeated or painful stimulation.

Pain and Sedation of Children in the Emergency Set- ting

Deep Somatic Pain

Spinal Dorsal Horn Pathways, Muscle and Joint

Deep Venous Thrombosis

Synonyms Blood clot; DVT

Definition

Commonly affects the lower leg and can present as a pain syndrome mimicking sciatica with primarily distal ex- tremity pain.

Postoperative Pain, Venous Thromboembolism

Sciatica

Default Value

Definition

Values attributed to a variable or data as a base value, which remains unless replaced by the user.

Definition of Disability (Adults)

Definition

The inability to engage in any substantial gainful activity by reason of any medically determinable physical or mental impairment or combination of impairments, which is expected to result in death or that has lasted or can be expected to last for a continuous period of not less than 12 months.

Disability Evaluation in the Social Security Admin- istration

Definition of Disability for Individuals under Age 18 (SSI Program Only)

Definition

A medically determinable physical or mental impairment or impairments that result in marked and severe functional limitations and that meet the duration re- quirement.

Disability Evaluation in the Social Security Admin- istration

Degenerative Disease

Definition

A biomechanical and pathologic condition caused by de- generation, inflammation, or infection.

Chronic Back Pain and Spinal Instability

Degenerative Joint Disease

Arthritis Model, Osteoarthritis

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532 Dejerine-Roussy Syndrome

Dejerine-Roussy Syndrome

Central Pain, Diagnosis

Dejerine-Sottas Syndrome (Neuropathy)

Synonyms DSN Definition

A severe form of inherited neuropathy that is clinically detected during infancy.

Hereditary Neuropathies

Delayed Muscle Soreness

Delayed Onset Muscle Soreness

JANFRIDÉN

Department of Hand Surgery, Sahlgrenska University Hospital, Göteborg, Sweden

jan.friden@orthop.gu.se Synonyms

Delayed Muscle Soreness; Exercise-Induced Muscle Soreness; DOMS

Definition

Delayed onset muscle soreness (DOMS) is the sensation of muscular discomfort and pain during active contractions that occurs 24–48 h after strenuous exercise. The initial symptoms are most evident at the muscle tendon junction and thereafter spread throughout the entire muscle. Muscle soreness and injury are associated with in- tense exercise and are more pronounced if the exercise performed is new to the individual.

Characteristics

Sore muscles after exercise are stiff, tender and aching, symptoms that are aggravated by active muscle contractions. The symptoms of DOMS develop during the first 24–48 h, , peak between 24 and 72 h and usually disappear without intervention within 5–7 days (Armstrong 1984; Ebbeling and Clarkson 1989; Fridén 1981). The soreness has been reported by some to be localized at the muscle-tendon junction, while others describe the pain as being diffusely spread throughout the muscle. Regardless of the exact location, palpation, passive stretching and renewed activity aggravate the

pain. Some controversy exists regarding the relation between maximum voluntary force and symptoms of soreness. Ebbeling and Clarkson suggested that there is no, or very little, relationship between the development of soreness and decrease of muscle strength (Ebbel- ing and Clarkson 1989). Return of maximum muscle strength to pre-exercise levels takes between 24 h and 2 weeks.

Bobbert and co-workers (Bobbert et al. 1986) reported an increase in limb volume 24–72 h h after eccentric activity of the calf. Intramuscular edema of the biceps, as verified by magnetic resonance imaging, is maxi- mized at 72 h after eccentric activity. The stiffness and swelling associated with DOMS is probably an effect due to edema occurring in the perimuscular connective tissue. Regardless of whether the swelling is intra- or extra-cellular, an increase in the intramuscular pressure is implicated. In addition to increased tenderness during palpation, the examiner will find prolonged strength loss, a reduced range of motion and elevated levels of creatine kinase in the blood. Frequently, muscle cramps accompany DOMS.

DOMS is primarily associated with the eccentric com- ponent of exercise (Asmussen 1952) During an eccentric action, a contracted muscle is forced to elongate while producing tension. Its counterpart, concentric action, produces tension during muscle shortening. The intermediate, isometric contraction, produces tension while the muscle remains essentially at the same length (Fig. 1). All three actions are common components of daily movement. The tension generated during eccentric action is higher than that for either of the other actions (Katz 1939) although fewer motor units are recruited (Bigland-Ritchie 1976).

Delayed Onset Muscle Soreness, Figure 1 Generalized relationship be- tween muscle length, force and velocity. Note the very high forces occurring at ”negative” velocities (from Fig. 6, Fridén and Lieber 1992, Med Sci Sports Exerc 24:521–530).

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Delayed Onset Muscle Soreness 533

Due to the nature of an eccentric action, the tension gen- erating mechanism can be expressed in two phases; the muscle contracts to generate tension and then the muscle is passively stretched by an external force while gener- ating additional tension.

It is still unknown whether the initial decline of strength after eccentric contractions (EC) is because of injury or fatigue or a combination of both. Some authors have referred the immediate loss of strength to overstretch of sarcomeres resulting in a non-optimal overlap between actin and myosin filaments. It has been suggested that during eccentric exercise some sarcomeres are stretched beyond overlap and thereby injured, while others maintain their length. Despite the great force loss after eccentric contractions, the resting membrane potentials of isolated muscles fatigued by eccentric or isometric contractions were similar (Warren et al.

1993). Since there is no evidence of excitation failure, the ability to produce action potentials is expected to be unaffected. Lieber and Fridén showed that it is not high force per se which causes muscle damage following eccentric contraction, but the magnitude of the active strain, i.e. strain during active lengthening (Lieber and Fridén 1993). The active strain hypothesis is described in terms of the interaction between the myofibrillar cytoskeleton, the sarcomere and the sarcolemma.

It is generally agreed that the initial force decline is due to mechanical injury. A number of mechanical factors such as muscle length, force and velocity seem to play roles in the consequences of eccentric contractions. Newham and colleagues found more pronounced strength loss after eccentric exercise at a long muscle length compared to a short muscle length (Newham et al. 1988). Although the nature of morphological injury to the muscle has been well documented and reported, the mechanism of the injury is not fully understood.

Strenuous exercise causes a disturbance of the muscle’s homeostasis. Although muscle tissue is extremely plas-

Delayed Onset Muscle Soreness, Figure 2 Schematic depiction of eccentric contraction-induced muscle damage. Muscle fiber strain results in disruption of the intermediate filament network. Disruption of the intermediate filaments causes loss of the sarcomere’s structural integrity and misalignment of striated bands.

tic, destructive changes in muscle ultrastructure may occur in response to unusual demands. DOMS and ul- trastructural disruptions are selectively associated with exercise involving EC (Fridén 1984; Fridén et al. 1981) and have been reported in both animal and human models. Such changes may require several weeks to resolve and often lead to muscle hypertrophy and strengthening.

In previous studies, two pieces of mechanical evidence suggested thatdesminplays a direct mechanical role in the force loss after EC (Fig. 2). Desmin immunostaining was rapidly lost, as fast as 15 min into a single bout of EC (Lieber et al. 1996) and a strong linear correla- tion was seen between the magnitude of desmin loss and loss of muscle force generated after EC. Recently, it has been hypothesized that there is a relationship between force loss, desmin immunostaining, transcriptional up- regulation and the ultimate increase in desmin content per sarcomere (Barash et al. 2002; Peters et al. 2003). Di- rect mechanical data demonstrated that reinforced sarcomeres are highly resistant to EC-induced injury.

In addition to injuries to muscle fibers, there is evidence of disturbance to muscle sense organs and of propriocep- tion after eccentric exercise. The peripheral contribution to perturbations of force perception after eccentric exercise is, however, small and the centrally derived sense of effort plays the most important role. Proske and Mor- gan made the common observation that a second period of exercise, for example 1 week after the first, produces much less damage (Proske and Morgan 2001). One pro- posed mechanism for this adaptation may be an increase in sarcomere number in muscle fibers. It is postulated that the adaptation is likely to lead to a secondary shift in the muscle’s optimum length for active tension. The authors conclude that the ability of muscle to adapt quickly after damage from a single bout of eccentric exercise im- plies the use in clinical applications of mild eccentric exercise for protecting a muscle against more major injuries.

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534 Delayed Severe Respiratory Depression

Nocifensive Behaviors, Muscle and Joint

Stretching

References

1. Armstrong RB (1984) Mechanisms of exercise-induced delayed onset muscular soreness: a brief review. Med Sci Sports Exerc 16: 529–538

2. Asmussen E (1952) Positive and negative muscular work. Acta Physiol Scand 28:364–382.

3. Barash IA, Peters D, Fridén J et al. (2002) Desmin cytoskeletal modifications after a bout of eccentric exercise in the rat. Am J Physiol 283:958–563

4. Bigland-Ritchie B, Woods JJ (1976) Integrated electromyogram and oxygen uptake during positive and negative work. J Physiol 260:267–277

5. Bobbert MF, Hollander AP, Huijing PA (1986) Factors in delayed onset muscular soreness of man. Med Sci Sports Exerc 18:75–81 6. Ebbeling CB, Clarkson PM (1989) Exercise-induced muscle

damage and adaptation. Sports Med 7:207–234

7. Fridén J (1984) Changes in human skeletal muscle induced by long term eccentric exercise. Cell & Tissue Res 236:365–372 8. Fridén J, Sjöström M, Ekblom B (1981) A morphological study

of delayed muscle soreness. Experientia 37:506–507 9. Katz B (1939) The relation between force and speed in muscular

contraction. J Physiol 96:45–64

10. Lieber RL, Fridén J (1993) Muscle injury is not a function of muscle force but active muscle strain. J Appl Physiol 74:520–526 11. Lieber RL, Thornell LE, Fridén J (1996) Muscle cytoskeletal disruption occurs within the first 15 minutes of cyclic eccentric contraction. J Appl Physiol 80:278–284

12. Newham DJ, Jones DA, Ghosh G et al. (1988) Muscle fatigue and pain after eccentric contractions at long and short length.

Clin Sci 74:553–557

13. Peters D, Barash I, Burdi M et al. (2003) Asynchronous functional, cellular and transcriptional changes after a bout of eccentric exercise in the rat. J Physiol 553:947–957

14. Proske U, Morgan DL (2001) Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications. J Physiol 537:333–345

15. Warren GW, Hayes D, Lowe DA et al. (1993) Mechanical factors in the initiation of eccentric contraction-induced injury in rat soleus muscle. J Physiol 464:457–475

Delayed Severe Respiratory Depression

Definition

Severe slowing or arrest of spontaneous breathing, usually caused by morphine administered close to the spinal cord (epidurally or directly into the cerebrospinal fluid)

Postoperative Pain, Acute Pain Team

Delirium

Definition

An acute or subacute syndrome with waxing and waning levels of consciousness, global cognitive impairment, a reduced ability to focus attention, sustain attention or to shift attention and disorganized wake-sleep cycle.

Cancer Pain, Assessment in the Cognitively Impaired

Cancer Pain Management, Overall Strategy

Delta(δ) Opioid Receptor(s)

Synonyms

OP1 receptors; DOP Definition

Receptors that preferentially bind enkephalins and enkephalin-like drugs. It was originally named for its discovery in the mouse vas deferens. The receptor was cloned in 1992. They are present throughout the telen- cephalon and spinal cord. Agonists are associated with spinal analgesia.

Opiates During Development

Opioid Receptors

Postoperative Pain, Transition from Parenteral to Oral

Delta(δ) Sleep

Definition

Delta sleep refers to stages 3 and 4 of non-REM (rapid eye movement) sleep.

Fibromyalgia

Demand Characteristics

Definition

This term refers to the demands of the situation that must be considered in the context of introducing hypnosis. Ex- perimental subjects tend to guess at the experimenter’s objectives and then behave accordingly in order to be socially compliant and co-operative. This tendency is clearly important in any therapeutic interaction where the patient may be trying to please the doctor.

Therapy of Pain, Hypnosis

Dementia

Definition

A syndrome characterized by a decline in multiple cognitive functions occurring in clear consciousness.

Cancer Pain, Assessment in the Cognitively Impaired

Demographic

Definition

Statistical characteristics of populations such as age, ed- ucational attainment or income.

Pain in the Workplace, Risk Factors for Chronicity, Demographics

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Demyelination 535

Demyelination

MATTHEWN. RASBAND¹, PETERSHRAGER² 1University of Connecticut Health Center, Farmington, CT, USA

2Department of Neurobiology and Anatomy, University of Rochester, Rochester, NY, USA

rasband@uchc.edu, pshr@mail.rochester.edu Definition

A large percentage of the axons in the nervous system are ensheathed by a lipid rich membrane called myelin. This sheath is essential for rapid and efficient conduction of electrical signals along axons. Demyelination is the loss of the myelin sheath and results from disease or injury.

Characteristics

Proper nervous system function depends on the trans- mission of electrical signals (action potentials) along axons and over relatively long distances. In order to facilitate conduction in a rapid and efficient man- ner, vertebrates have developed a lipid rich sheath, called myelin, which confers several passive electrical properties onto axons. These properties include high membrane resistance and low membrane capacitance. Myelin also plays several active roles that determine axonal excitability. For example, myelin- axon interactions restrict sodium (Na+) channels to regularly spaced gaps in the myelin sheath called nodes of Ranvier (Fig. 1a, arrow), and compact myelin regulates the kinds of Na⁺channels expressed in axons (for a more comprehensive review, see Salzer 2003).

Together, these active and passive properties facilitate rapid and efficient action potential conduction by de- creasing loss of electrical charge in regions covered by myelin, and by regenerating the action potential at each node of Ranvier.

Myelin is made by glial cells: Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). Demyelination, or loss of the myelin sheath, is most commonly associated with autoimmune diseases (e.g. multiple sclerosis (MS) in the CNS and Guillain-Barre syndrome in the PNS) or traumatic injury (e.g. spinal cord crush), but may also be a consequence of mutations in a variety of myelin proteins (e.g. various types of Charcot-Marie-Tooth disease). In most cases of demyelination in the PNS, Schwann cells are able to remyelinate axons. In contrast, in the CNS, oligodendrocytes are much less efficient at remyelination. This is thought to be a consequence of differences between the PNS and CNS extracellular environments, as well as intrinsic differences between

Schwann cellsand oligodendrocytes.

Subsequent to demyelination, the passive electrical properties of axons are dramatically altered, resulting in failure to conduct action potentials through de-

myelinated zones. In particular, demyelination causes a striking increase in the axonal membrane capacitance.

Thus, as electrical signals propagate down an axon, the current available to trigger the next group of Na⁺channels is reduced due to capacitative charging of the axonal membrane. Demyelination also results in dysregulation of myelin’s ‘active’ properties. It may be that disruption of these ‘active’ properties contributes to the generation of neuropathic pain following demyelination.

While alterations to the passive properties of axons after demyelination are well understood, the consequences for the active properties of myelin are mostly unknown.

As a result, recent work has focused on how myelin- axon interactions regulate the excitable properties of axons. For example, a variety of experimental models have been used to investigate the consequences of demyelination and remyelination on Na⁺channel clustering and expression.

Acute Demyelination

Peripheral demyelination has been shown to dramatically influence the localization of ion channels. For example, injection of the weak detergent lysolecithin into a peripheral nerve causes a transient, focal demyelinated lesion about 1 week after the injection. This lesion can be remyelinated by Schwann cells during the second and third weeks post-injection. However, the architecture of this new myelin is somewhat different than before: sheaths are thinner and shorter (Fig. 1b) (Dugandzija-Novakovic et al. 1995). Therefore, in order to support action potential conduction, new nodes of Ranvier with high densities of Na⁺ channels must be formed in regions that were formerly covered by compact myelin and characterized by a low density of channels (Fig. 1b, arrowheads) (Shrager 1989). This model has permitted a careful analysis of Na⁺channel localization subsequent to acute demyelination and during remyelination (Dugandzija-Novakovic et al.

1995). Specifically, regions of demyelinated axon can be seen to retain Na⁺ channel clusters. Some of these clusters even appear indistinguishable from those found in normal axons (Fig. 1c), suggesting that in the ab- sence of overlying myelinating Schwann cells, neurons have intrinsic mechanisms that cause clusters of Na⁺ channels to be retained. In other places, Na⁺ channel clusters (Fig. 1d, arrow) can be seen to have a ‘tail’ of immunoreactivity leading away from the main cluster (Fig. 1d, arrowheads). This situation is most often seen adjacent to heminodes (where the myelin on one side of a node has been lost and the sheath on the other side remains intact). As remyelination occurs, single axons can be seen to have multiple Na⁺channel clusters between remyelinating Schwann cells (Fig. 1e; the two Na⁺ channel clusters identified by the arrowheads are found in the same axon and are only about 25μm apart).

As remyelination progresses, these clusters appear to be ‘pushed’ ahead of the myelinating Schwann cell

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536 Demyelination

Demyelination, Figure 1 Na⁺ channel clusters in myelinated, demyelinated, and remyelinating peripheral axons. (a) A node of Ranvier (arrow) labeled for Na⁺ channels. The outline of the myelin sheath can also be seen. (b) Cartoon illustrating that remyelinated axons have shorter and thinner sheaths with new nodes of Ranvier in formerly internodal zones. (c) A Na⁺ channel cluster in a demyelinated axon. (d) A heminode with a Na⁺ channel cluster (arrow) and ‘tail’

of Na⁺channel immunoreactivity (arrowheads). (e) Two Na⁺channel clusters (arrowheads), located on the same remyelinating axon. (f) Two Na⁺channel clusters just before they fuse to form a new node of Ranvier. Scalebars = 10μm.

until they finally fuse and form a new node of Ranvier.

Figure 1f shows two Na⁺channel clusters (11 days after lysolecithin injection) just before they fuse at a nascent node of Ranvier.

Chronic Demyelination

One major difference between lysolecithin mediated demyelination and many forms of disease or injury related demyelination is that the latter forms are usually chronic. As a result, lessons learned from acute demyelination may not be generally applicable to chronic demyelination. To date, few studies have focused on

the consequences of chronic demyelination for Na⁺ channel expression and localization. Some of the first experiments relied on mutant dysmyelinating mice to assess these characteristics. For example, we showed that the localization of Na⁺channels was dramatically disrupted in axons of the hypomyelinated mouse mutant Shiverer (Rasband et al. 1999). Further, Westenbroek et al. (1992) showed that the expression of one particular type of brain Na⁺ channel (Nav1.2) was dramatically increased in these mice. However, subsequent studies demonstrated that during normal development, Nav1.2 is found in premyelinated and actively myelinating

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D

Dendritic Spines 537

axons (Boiko et al. 2001). Therefore, the differences in Na⁺channel expression and localization seen inShiv- erer may be related to developmental defects, rather than a consequence of demyelination.

To directly address whether chronic demyelination can influence the kinds of Na⁺ channels present in CNS axons, Craner et al. (2003) examined the localization of Nav1.2 and Nav1.6 in an inflammatory mouse model of CNS demyelination [ experimental allergic en- cephalitis(EAE)], and Rasband et al. (2003) examined localization and expression levels of these same Na⁺ channels in a genetic, adult onset model of chronic CNS demyelination. Each of these studies showed essentially the same result: that chronic demyelination results in a loss of clustered Na⁺ channels, but a concomitant increase in Nav1.2 expression levels. Indeed, Rasband et al. (2003) showed a 6-fold increase in their model of the amount of Nav1.2 found in chronically demyelinated optic nerve axons. These Nav1.2 channels were found diffusely distributed throughout the axon rather than in clusters. Together, these studies suggest that, in addition to altering the passive electrical properties of axons and the active clustering of Na⁺channels to nodes of Ranvier, myelin also regulates the kinds of channels present in CNS axons. The axon-glia signaling that me- diates this regulation of channel expression, trafficking, and/or localization is an active area of investigation.

Demyelination and Neuropathic Pain

A very common symptom associated with MS is the presence of acute and/or chronic pain (e.g.trigeminal neuralgia). Similarly, some forms of Charcot-Marie- Tooth disease, characterized bysegmental demyeli- nationof PNS axons, also have as symptoms the development of hyperalgesia, spontaneous pain, and

allodynia. Unfortunately, very little is known about the molecular and cellular mechanisms linking demyelination and neuropathic pain. Since the expression and localization of Na⁺ channels appears to depend on interactions with myelinating glial cells, and Na⁺ channels are obvious candidates to modulate neuronal hyperexcitability, one intriguing possibility is that pain associated with demyelination is a consequence of loss of neuroglial interactions.

Recently, Wallace et al. (2003) showed that acute PNS demyelination by lysolecithin results in the development of both allodynia and hyperalgesia. The development of the neuropathic pain coincided with detection of Nav1.3 Na⁺channels in formerly myelinated axons – a surprising result since Nav1.3 is not normally found in myelinated nerve fibers, or anywhere else in the adult nervous system. Further, spontaneous action potentials were measured during the remyelination phase. These results suggest that peripheral demyelination may lead to aberrant Na⁺ channel subtype expression and activity, and the switching of receptor modality from proprioceptor or mechanoreceptor to nociceptor.

Although very little is known about the development of neuropathic pain as a consequence of demyelination, fu- ture studies designed to determine the molecular and cellular mechanisms underlying control of both Na⁺channel localization and expression may lead to the ability to directly modulate neuronal activity. However, one thing is clear: in the arena of neuropathic pain, myelinating cells such as Schwann cells and oligodendrocytes are not simply bystanders, but instead play active roles by modulating the excitable properties of sensory neurons.

References

1. Boiko T, Rasband MN, Levinson SR et al. (2001) Compact Myelin Dictates the Differential Targeting of Two Sodium Channel Isoforms in the Same Axon. Neuron 30:91–104 2. Craner MJ, Lo AC, Black JA et al. (2003) Abnormal Sodium

Channel Distribution in Optic Nerve Axons in a Model of In- flammatory Demyelination. Brain 126:1552–1561

3. Dugandzija-Novakovic S, Koszowski AG, Levinson SR et al.

(1995) Clustering of Na⁺Channels and Node of Ranvier For- mation in Remyelinating Axons. J Neurosci 15:492–503 4. Rasband MN, Kagawa T, Park EW et al. (2003) Dysregulation

of Axonal Sodium Channel Isoforms after Adult-Onset Chronic Demyelination. J Neurosci Res 73:465–470

5. Rasband MN, Peles E, Trimmer JS et al. (1999) Dependence of Nodal Sodium Channel Clustering on Paranodal Axoglial Con- tact in the Developing CNS. J Neurosci 19:7516–7528 6. Salzer JL (2003) Polarized Domains of Myelinated Axons. Neu-

ron 40:297–318

7. Shrager P (1989) Sodium Channels in Single Demyelinated Mammalian Axons. Brain Res 483:149–154

8. Wallace VC, Cottrell DF, Brophy PJ et al. (2003) Focal Lysolecithin-Induced Demyelination of Peripheral Afferents Results in Neuropathic Pain Behavior that is Attenuated by Cannabinoids. J Neurosci 23:3221–3233

9. Westenbroek RE, Noebels JL, Catterall WA (1992) Elevated Ex- pression of Type II Na⁺Channels in Hypomyelinated Axons of Shiverer Mouse Brain. J Neurosci 12:2259–2267

Dendrite

Definition

Dendrite refers to the post-synaptic element of a neuron.

Opioid Receptor Trafficking in Pain States

Dendritic Spines

Definition

Small protrusions of the dendritic shafts specialized at the reception and processing of incoming signals at synapses. They most often look like pedicled knobs, but may also assume other configurations such as sessile knobs, rose spines, or bunches of knobs connected to a sole pedicle.

Spinothalamic Tract Neurons, Morphology

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538 Dendritic Topography

Dendritic Topography

Definition

Spatial distribution of the dendritic tree with respect to the cell body and gray matter regions located around it.

Dendritic Tree

Definition

Ensemble of neuronal processes ramifying around the cell body and specialized to receive input (chemical or electrical signals) from other neurons.

Dendrogram

Definition

A dendrogram hierarchically organizes stimulus ob- jects, subclusters, clusters, etc. on the basis of their relative similarities.

Multidimensional Scaling and Cluster Analysis Ap- plication for Assessment of Pain

Denervation

Definition

Situation where a limb (or an organ or part of it) is ren- dered insensitive to applied stimuli by severing sensory axons that innervate the limb. Sensory endings rapidly degenerate in the process of anterograde (Wallerian) de- generation.

Facet Joint Pain

Denervation Model of Neuropathic Pain

Densocellular Subnucleus of the Mediodorsal Nucleus

Synonyms MDdc

Definition

Envelops MD laterally and posteriorly. Its neurons re- semble those of the central lateral nucleus (CL). MDdc receives input from many of the same subcortical sites as CL, and projects to the striatum and to premotor cortical areas.

Spinothalamic Terminations, Core and Matrix

Dental Pain, Etiology, Pathogenesis and Management

GRAHAMR. HOLLAND

Department of Cariology, Restorative Sciences &

Endodontics, School of Dentistry, University of Michigan, Michigan, MI, USA

rholland@umich.edu Synonyms

Toothache; pulpitis; Pulpalgia; dentin sensitivity Definition

A noxious experience that originates or appears to orig- inate from a tooth.

Characteristics

Pain is not experienced from an entirely healthy tooth under normal physiological conditions, but can be induced by a cold stimulus at 0˚C or below. It is more readily felt in otherwise normal teeth in which thedentinbe- neath the enamelof the crown or thecementumof the root is exposed. Then hot stimuli may, and osmotic and cold stimuli will, induce pain. This pain is sharp and lasts only for the duration of the stimulus. If thedental pulp, the soft tissue within the dentin and responsible for its production, is inflamed, the pain to an applied stimulus will be strong, dull and throbbing. It may con- tinue beyond the duration of the stimulus and may be present spontaneously. As the majority of nociceptors in the uninjured pulp are inactive they can be classified as silent. No sensations other than pain can be experienced from the tooth pulp in response to non-electrical stimuli, a property that has been utilized in a number of experimental studies. The stimuli capable of inducing pain from inflamed pulps would not be in the noxious range when applied to intact, healthy skin. It is difficult to elicit pain from a freshly cut cavity in dentin, but the tooth becomes much more responsive if bacteria are al- lowed to inhabit the cavity for a week to allow the underlying pulp to become inflamed (Anderson et al. 1967).

The intensity of pain felt from a tooth with an inflamed pulp is highly variable but it has been ranked using the McGill pain questionnaire as similar to the pain experienced from arthritis or a bone fracture but substantially less than that associated with childbirth (Melzack 1984).