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Pain is subjective • Self-experience • Experience depends on circumstances • Pain can cause many different reactions: – Activate autonomic system (heart rate, blood pressure, sweating, etc.) – Muscle activity – Mood (fear, anxiety, depression) – Prevent sleep Pain occurs with different degrees of severity • Mild pain: Does not interfere noticeably with everyday life • Moderate pain: May cause some annoyance and perceived as unpleasant • Severe chronic pain: Affects a person’s entire life in major ways There are many forms of pain • Mild pain: Does not interfere noticeably with everyday life • Moderate pain: May cause some annoyance and may be perceived as unpleasant • Severe pain: Affects a person’s entire life in major ways Different forms of pain • • • • • Acute pain Chronic pain Somatic pain Neuropathic pain Central neuropathic pain Pain has many different forms, but the same name Tinnitus has many different forms but the same name There are different types of pain • Somatic and visceral pain (Stimulation of nociceptors) – Pain ceases when stimulation ceases • Neuropathic pain – Pain is related to the nervous system • Central neuropathic pain – Plastic changes in the function of the CNS – May be persistent It is important to have different names for for different disorders • We cannot think about matters that do not have names • The same words is used to describe very different forms of tinnitus and pain • Using the same names for fundamentally different disorders is a disadvantage in studying and treating such disorders Severe pain affects a person’s entire life in major ways • • • Prevent or disturb sleep Interfere with or prevents intellectual work May cause suicide May involve limbic structures causing affective reactions Often accompanied by abnormal sensations from touch How prevalent is severe pain? Some pain was reported by 86% of individuals above the age of 65 (Iowa study, 1994) The prevalence of severe pain was 33% for people at age 77 and above (Swedish study, 1996) How prevalent is severe pain? Some pain was reported by 86% of individuals above the age of 65 (Iowa study, 1994) The prevalence of severe pain was 33% for people at age 77 and above (Swedish study, 1996) Pain “The only tolerable pain is someone else’s pain” René Leriche, French surgeon, 1879–1955 There are different types of pain • Somatic and visceral pain (Stimulation of nociceptors) – Pain ceases when stimulation ceases • Neuropathic pain – Pain is related to the nervous system • Central neuropathic pain – Plastic changes in the function of the CNS – May be persistent Pain Stimulation of nociceptors Somatic pain Viscera pain Fast pain slow pain Referred pain Muscle pain Non-nocicieptor pain Inflamatory Neuropathic pain Lesions to nerves or cns Central neuropathic pain • Central neuropathic pain: – Pain sensation caused by abnormal neural activity in the CNS • Hyperacusis: – Sounds are perceived louder than normal • Allodynia: – Sensation of pain from normally innocuous stimulation (such as light touch) • Hyperpathia: – Exaggerated and prolonged reactions to painful stimuli Somatic and visceral pain (Stimulation of nociceptors) • • • • • Burning (temperature) Injury Inflammation Chemicals Compression of spinal nerve roots (nervi nervorum) Muscle pain Relationship between commonly used terms to characterize muscle tension: Tone, stiffness, contracture, and spasm MUSCLE TONE (general tone) Contractile activity Viscoelastic tone (specific tone) Elastic stiffness Viscoelastic stiffness Contracture (no EM G activity) Electrogenic spasm (pathological) Electrogenic contraction (normal) Tension type headaches with trigger zones in the temporalis muscle (), in suboccipital, sternocleidomastoid and upper trapezius muscles (), from where pain attacks can be elicited Neuropathic pain • • • • • Pain of the nervous system Neuralgias Anesthesia dolorosa Root pain Stroke pain Neuropathic pain • All pain of neural origin The term is mostly used by neurologists for pain caused by disorders of peripheral nerves and cranial nerves Normal Neuropathic Central neuropathic pain • Plastic changes in the function of the CNS (WDR neurons, thalamus) Acute pain may promote development of central neuropathic pain • Central neuropathic pain is a neurologic disorder Acute pain sensation may not be a sign of pathology • • Pain sensation can be elicited by: Stimulation of nociceptors Overstimulation of other receptors Acute pain has two phases: A fast (sharp) and a slow (burning) sensation • The slow and delayed pain is mediated by unmyelinated fibers (C-fibers). • The fast phase is mediated by myelinated fibers (A). First pain Second pain DRG C fiber Ad fiber DRG Time DRG X DRG Time DRG X DRG Time Fast and slow pain are different • Fast pain (stinging): – Well defined with regards to location – Its strength is defined • Slow pain (aching): – Diffuse, poorly localized anatomically – Difficult the estimate its strength Different types of nerve fibers carry different kinds of pain Temperature There are four different temperature receptors: Cool and warmth (sensory receptors) Cold and heat (nociceptors) Temperature 1. 2. 3. 4. Cool and warmth receptors mediate sensation of temperature Cold and heat receptors are nociceptors that mediate sensation of pain. Cool and warmth receptors are innervated by small myelinated (A fibers, diameter 1-5 m, conduction velocity 5-30 m/sec). Cold and heat receptor are innervated by unmyelinated fibers (C-fibers, diameter 0.2-2 m; conduction velocity 0.5-1 m/sec). Receptors DRG Wide dynamic range neuron THE ANTERIOR LATERAL SYSTEM MEDIATES PAIN SENSATIONS The spinothalamic tract is the best known of the anteriorlateral tracts Midline Association cortex Spinothalamic tract SI cortex Dorsal thalamus Ventral thalamus PAG Brainstem reticular formation Spinothalamic tract DRG Receptor Dorsal horn Cortex Midline Association cortex Nonspecific (dorsal) thalamic nuclei SI cortex Dorsal thalamus Ventral thalamus Reticular formation PAG Brain stem Anterolateral funiculus Brainstem reticular formation Spinal cord Spinothalamic tract DRG Receptor Dorsal horn Trigeminal nerve Spinal nerves Cerebral cortex Thalamus Trigeminal ganglion Midbrain Motor nuclei RF Spinalcord Brainstem Ascending projections of the anterior portion of the STT from neurons in lamina IV-V of the spinal horn. VPI: Ventral posterior inferior (nuclei of thalamus); VPL: Ventral posterior lateral (nuclei of thalamus); SI: Primary somatosensory cortex; SII: secondary somatosensory cortex SI MIDLINE VPL SII VPI Brainstem I II Anteriror portion of STT MIDLINE 3a (SI) Projections of the lateral portion of the STT from cells in lamina I of the dorsal horn Area 24c Thalamus VPI VMpo Dorsal Anterior insula PAG Brainstem Lateral portion of STT I II MIDLINE SI (contralat.) SII (ipsilateral) SII (contralat.) Projection of unmyelinated C fibers. VPI VMpo Notice: Projection to SII is bilateral but only the SI receives input from C fibers Lateral portion of STT I II DRG Association cortex Midline Spinoreticular tract SI cortex Dorsal thalamus Reticular formation of pons Reticular formation of melulla DRG Receptor Dorsal horn Midline Spinomesencephalic tract Hypothalamusamygdala limbic system Periaqueductal gray PAG DRG Receptor Dorsal horn Limbic system Association cortex SMP Prefrontal cortex Pathways involved in mediating the sensation of nociceptor pain SII "WHAT" SI cortex Dorsal thalamus "WHERE" Ventral thalamus Medial lemniscus Reticular formation AROUSAL Anterior lateral tract Frontal lobe Amygdala Input to the Hypothalamus periaquaductal gray (PAG) and pathways that modulate transmission of pain signals by the PAG through the rostral ventromedial medulla (RVM) pathway. Locus coeruleus PAG Nucleus cuneiformis Pontomedular reticular formation RVM From nociceptors Ascending pain pathways DRG Dorsal horn PAG Dorsolateral pontomesencephalic tegmentum pathway (DLTP). DLPT From nociceptors Ascending (crossed) pain pathways Dorsal horn DRG Descending pathways from raphe nucleus From raphe (NA-serotonin pathway) nucleus To thalamus NA serotonin pathway Lamina I interneuron Nociceptor fiber Post synaptic inhibition DRG Presynaptic inhibition Lamina II interneuron Forebrain Forebrain NST Thalamus Innervation by the vagus nerve of organs in the lower abdomen involving the nucleus of the solitary tract (NST) NA-serotonin pathway Spinal pain neuron DLF: Dorsolateral funiculus VLF: Ventrolateral funiculus RVM: Rostroventral medulla Visceral pain is different from somatic pain • Inconsistent sensations • Sometimes referred pain to body surface • Often inescapable Visceral afferent innervation in the DRG lower body and motor (efferent) Viceral innervation. Spinal cord T11-L4 Viceral afferents afferents S 3-S 4 DRG Viceral afferents Uterus Efferent Viceral receptors Pain fibers Bladder Nociceptors Thalamus Two-way connections between PAG, DLPT and RVM and their connections to the dorsal horn PAG DLPT NE non NE RVM 5HT non 5HT _ + Dorsal horn Primary afferents The dual input to dorsal horn cells from RVM On-neuron (Morphine inhibits) Off-neuron (Morphine excites) From nociceptor Thalamus Nocieptive dorsal horn neuron DRG Spinothalamic tract activate dorsomedial thalamus STT Reticular formation Dorsomedial thalamus Association cotices Cingulate gyrus PAG Hypothalamus Amygdala Hypothesis about expansion of receptive field and creation of trigger points by unmasking of dormant synapses Cerebral cortex Cortical receptive field Cortex Spinal cord DRG Receptive fields Mean EMG amplitudes recorded from a muscle at a trigger point and at an adjacent non-tender muscle 46.21 (5.92) 50 T rigger point Adjacent non-tender muscle 45.59 (8.06) 40 30 20 10 0 7.53 (0.36) 3.83 (0.94) Normal subjects N=8 6.08 (1.08) T ension headache patients N=29 4.84 (0.52) Fibromyalgia patients N=25 Itch • The basis of itching is poorly understood but it has similarities with pain. CENTRAL NEUROPATHIC PAIN MAY INVOLVE THE SYMPATHETIC NERVOUS SYSTEM • REFLEX SYMPATHETIC DYSTROPHY, RSD Role of sympathetic nervous system in neuropathic pain 1. Sympathetic system is activated by stimulation of pain fibers 2. Sympathetic fibers secrete nor-epinephrine near mechanoreceptors 3. Sensitivity of mechanoreceptors increases 4. Activation of sympathetic system increases 5. Result: A viscous circle that causes RSD Increased activity Activation of the sympathetic nervous system Nociceptor sensitization Liberation of noradrenalin Trauma cause activation of pain fibers (C-fibers), which sensitize WDR neurons Sensitized WDR neurons cause pressure to activate pain circuits (allodynia) Mechanoreceptors are activated by epinephrine that is secreted from sympathetic nerves in absence of mechanical stimulation Contemporary hypotheses of neural mechanisms involved in generating CRPS I and II following trauma Central lesion Chronic excitation of visceral and deep somatic afferent s T rauma with/wit hout peripheral nerve lesion ABNORMAL ST AT E OF AFFERENT NEURONS Pain Sympathetic block DIST ORT ED INFORMAT ION PROCESSING IN SPINAL CORD Abnormal regualation of blood flow and sweating MOVEMENT DISORDERS ABNORMAL ACT IVIT Y IN MOT ONEURONS T O SKELET AL MUSCLE ABNORMAL SYMPAT HET IC ACT IVIT Y (VASO-SUDOMOT OR ORT HER ABNORMALIT IES? CRPS: Complex regional pain syndrome Swelling T rophic changes Neuropathic pain • • • • • Pain of the nervous system Neuralgias Anesthesia dolorosa Root pain Stroke pain Central neuropathic pain • Plastic changes in the function of the CNS (WDR neurons, thalamus) Central neuropathic pain • All pain of neural origin The term is mostly used for pain caused by disorders of peripheral nerves and cranial nerves Central neuropathic pain may be caused by: • • • Chronic inflammation Sensitization of skin receptors Changes in the connectivity of the CNS (through neural plasticity) Acute pain may promote development of central neuropathic pain • Central neuropathic pain is a neurologic disorder Wide dynamic range neurons Central neuropathic pain may develop from peripheral nerve injuries • The pain is referred to the peripheral location • Treatment of that location will not help • The patient and the surgeon are both frustrated Central neuropathic pain may involve changes in function • • Normally innocuous stimulation becomes painful (allodynia) Stimuli that normally cause mild pain cause an exaggerated reaction (hyperpathia) Central neuropathic pain is often accompanied by altered perception of touch and pain stimuli • Touch may cause pain (allodynia) • Increased sensitivity to pain (hyperalgesia) • Painful stimulation may cause exaggerated reaction to pain and prolonged pain (hyperpathia) Central neuropathic pain may involve changes in function • • Normally innocuous stimulation becomes painful (allodynia) Stimuli that normally cause mild pain cause an exaggerated reaction (hyperpathia) Allodynia: Pain from normally innocuous stimulation (of the skin) Hyperalgesia: Extreme sensitiveness to painful stimuli. Hyperpathia: Exaggerated subjective response to painful stimuli, with a continuing sensation of pain after the stimulation has ceased. Temporal integration Normal Neuropathic pain Pain Tingling From: Møller and Pinkerton, 1997 Temporal integration during development of carpal tunnel syndrome A B From: Møller and Pinkerton, 1997 Hyperalgesia from experimentally induced burns B A Before burn After burn 14 12 10 8 6 4 Mechanical hyperalgesia Flare C A B 2 D Site A 1 cm Site B Site C Hypothesis for referred pain and sensitization of different nociceptors Sensitization • Peripherally: – Receptors • Centrally – Increased synaptic efficacy – Expression of new neurotransmitters – Neuromodulators – Morphological re-organization Other phenomena associated with chronic pain • “Wind-up” – Response to second stimulus is stronger than the response to the first one • Change in temporal integration From: Møller: Sensory Systems, 2002 "Wind-up" is NMDA mediated. Response with and without an NMDA antagonist. Control NMDA antagonist 40 30 20 10 0 0 10 Stimulus number 20 Severe neuropathic pain affects a person’s entire life in major ways • • • Prevent or disturb sleep Interfere with or prevent Intellectual work Involve limbic structures causing affective reactions How do we explain these symptoms and signs physiologically and anatomically? Where is the neural activity that give a sensation of pain generated? The anatomical location of the abnormality that cause pain may be different from that to which the pain is referred • Referred pain • Central neuropathic pain The abnormal neural activity that causes symptoms are not generated at the location where the symptoms are felt Example: • Posttraumatic central neuropathic pain • Phantom pain Central pain pathways for pain • PROJECT TO PRIMARY CORTICES WITH SPATIAL INFORMATION (“WHERE”) • PROJECT OBJECTIVE INFORMATION (“WHAT”) TO MANY DIFFERENT PARTS OF THE CNS. • NON-CLASSICAL PATHWAYS ALSO CONTRIBUTES TO AROUSAL SUMMARY OF PATHWAYS INVOLVED IN MEDIATING THE SENSATION OF PAIN CENTRAL PAIN PATHWAYS PROJECT TO PRIMARY CORTICES WITH SPATIAL INFORMATION (“WHERE”) OBJECTIVE INFORMATION (“WHAT”) TO MANY DIFFERENT PARTS OF THE CNS (FOR EXAMPLE THE AMYGDALA) NON-CLASSICAL INFORMATION ALSO CONTRIBUTES TO AROUSAL From: Møller: Sensory Systems, 2003 Reversal of neural plasticity • “TENS” (transderm electric nerve stimulation) has been used for many years in treatment of chronic pain • Recently, sound stimulation in various forms have been introduced in treatment of severe tinnitus Severe neuropathic pain affects a person’s entire life in major ways • • • Prevent or disturb sleep Interfere with or prevent Intellectual work Involve limbic structures causing affective reactions How can pain information reach the amygdala? • Through the thalamus • Through routes that are enhanced by expression of neural plasticity (re-routing of information) Connections from a sensory system to the amygdala “the high route” From: Møller: Sensory Systems, 2003 Connections from a sensory system to the amygdala “the low route” From: Møller: Sensory Systems, 2003 The amygdala is involved in fear and other mood disorders Connections from the amygdala From: Møller: Sensory Systems, 2003 INESCAPABLE PAIN INVOLVES OTHER PARTS OF THE CNS THAN ESCAPABLE PAIN Activate different columns in the PAG coordinating either active of passive coping