From Ch. 22 “Principles of Neural Science”, 4th Ed. Kandel et al The bodily senses From Ch. 22 “Principles of Neural Science”, 4th Ed. Kandel et al

Bodily senses Bodily senses = somatic sensation Sensory information Large variety of receptors Distributed throughout the body Sensory information Nerves transmit information from the receptors by frequency modulation of electrical signals (action potentials)

Dorsal root ganglion (DRG) DRG contains the cell bodies of sensory neurons All somatosensory information from limbs and trunk are transmitted via DRG Stimulus transmission from sensory receptor to CNS Primary afferent neuron has two branches to Periphery Spinal cord

The sensory receptor Peripheral receptor Located at the terminal of the sensory neuron Molecular specialization that transforms one type of energy into action potentials Special transducer molecules

Somatic receptor types Fiber classification Conduction velocity (skin) or fiber diameter (muscle) Myelinated or unmyelinated 4 major modalities (distinct system of receptors and pathways to the brain) Discriminative touch (size, shape, texture, movement across skin) Proprioception (joint position) Nociceptors (tissue damage, inflammation, chemical irritation, pain, itch) Thermal receptors (warm, cold)

Somatic receptor types 1 2 3 4

Somatic receptor types 1 2 3 4

Somatic receptor types 1 2 3 4

Nerve endings and fiber types Bare nerve endings Thermal and painful (nociception) sensations Encapsulated nerve endings Touch and proprioception Deformation of receptive surface Large diameter myelinated axons (rapid conduction) Mechanoreceptors (touch, greatest density in glabrous skin [hairless], finger tips, lips) Proprioceptors (joint position) Small diameter myelinated and unmyelinated (slow conduction) Thermal receptors Nociceptors

Location of nerve endings

Mechanoreceptors Specialized organs surrounding the nerve endings Sensitive to displacement/ deformation 4 major types in glabrous skin Superficial location (located below skin ridges) Meissner corpuscle – in glabrous skin Rapidly adapting, fluid filled structure, sense deformation of small areas Merkel disk receptor - in glabrous skin and hairy skin Slowly adapting, sense sustained pressure, salient bumps, sharp edges Deep subcutaneous location (less numerous) Pacinian corpuscle Similar to Meissner corpuscle, rapid indentation, minute vibration, frictional displacement, small irregularities (edges/ corners) Ruffini ending Slowly adapting, links folds in skin at the joints, sense stretch and bending, shape of grasped objects, global properties of objects, wide area of skin

Mechanoreceptors Deep receptors sense deformation of a wider skin area that extends beyond the overlying ridges Nerve fibers to superficial layers branch off to several nearby sensory receptors Nerve fibers in subcutaneous layers only innervate one receptor 4 types of mechanosensitivity Gentle touch of skin (well-localized) Vibration (frequency and amplitude) Texture (discrimination with fine spatial detail, two-point discrimination) Shape of objects grasped

Receptive field (RF) Size and structure of RF vary Large, central zone with max sensitivity Small, well- localized Direction- specific stretch Size and structure of RF vary

Receptive field (RF) Size and structure of RF vary Large, central zone with max sensitivity Small, well- localized Direction- specific stretch 2-3 mm diameter 10 mm diameter Relative sensitivity to pressure Central zone with large continuous surface Directly above receptor 10-25 receptors Fine spatial differences coarse spatial differences Size and structure of RF vary

Receptor distribution Most numerous receptor types Fine spatial sensitivity Best at finger tips Uniform distribution Finger tips are the most densely innervated region of the skin 300 mechanoreceptive nerve fibers per square centimeter

Two-point discrimination Min distance as which 2 stimuli can be resolved as distinct Determine if one or more points are stimulated Spatial resolution depends on the RF size/ receptor density Spatial resolution of stimuli varies across the body Smallest receptive fields in fingers, lips, and tounge April 15, 2009

Vibration sense Vibration is coded by spike trains Each AP signals one sinusoidal cycle Vibration frequency is signalled by the AP frequency Different receptors have different sensitivity Merkel: 5-15 Hz Meissner: 20-50 Hz Pacinian: 60-400 Hz Detection depends on size of skin indentation and frequency Detection threshold = tuning threshold = Lowest stimulus intensity that evokes one AP/ cycle Intensity of vibration depends on the total number of nerve fibers activated Sensory threshold April 15, 2009

Adaption and threshold Slowly adapting (SA) Constant pressure Rapidly adapting (RA) (1) Adapting at the beginning and end of stimulus (2) Encode sense of motion of object - Fires when position change (firing rate proportional to speed) - Stops firing when object is at rest AP/ sec depends on indentation force Sensory threshold The minimum stimulus intensity generating an AP RA’s have lowest touch threshold Pacinian corpuscles are the most sensitive mechanoreceptor

Shape and size Constant force P= F/a At constant force (F), the smaller area (a) stimulated results in bigger pressure (P) => higher firing rate Strong initial response Firing rate is proportional to the curvature of each probe April 15, 2009

Spatial characteristics Smaller Receptive field diameter Bigger Higher Spatial resolution Lower Texture, size, and shape are signalled by population of receptors Periodic firing of groups of receptors signal the spatial characteristic Active and inactive receptors contribution The individual receptor is only stimulated by a part of the pattern The spatial resolution depends on receptor density and type of receptor Natural stimuli rarely activates a single receptor alone April 15, 2009

Example: lifting an object Lifting and object Grasp, force increase, object lifted, vertical gravitational pull, force decrease, release Grasp and release Meissner c. : contact/ release; increased grasp force Pacinian c. : transient pressure at start/ stop Grip force Merkel disks: continous firing/ proportional with force Gravitational pull Ruffini endings: slowly adapting, sense stretch

Somatic receptor types 1 2 3 4

Thermal receptors 4 thermal sensations: cold, cool, warm, hot Constant temperature Adaption Tonic discharge/ steady rate Body temperature Continuously low rate Cold fibers more active Most sensitive to changes in temp than constant temp Warm fibers: Range, 29-49 deg Peak/ preferred, 45 deg Cold fibers: Range 5-40 deg Peak/ preferred, 25 deg Peak sensitivity Adaption Silenced Encoding of temperature involves comparing the relative activity of different populations

Somatic receptor types 1 2 3 4

Mechanical nociceptor Nociceptors Information about stimuli that can damage tissue are conveyed by nociceptors Chemicals are released from traumatized tissue E.g. Substance P, histamine, and bradykinin 2 overall types: Nociceptive specific Wide dynamic range neurons 3 classes of nociceptors Mechnical: pinch, punctate, squeeze Thermal: above 45 deg or below 5 deg Polymodal: mechanical, thermal, chemical Mechanical nociceptor

Somatic receptor types 1 2 3 4 Proprioception: sense of position and movement of one’s own limbs wo. Vision (1) static limb position, (2) limb movement (kinesthesia); in muscle and joints April 15, 2009

Afferent fibers Different size and conduction velocity of axons Large fibers conduct faster than small/ thin fibers because the internal resistance to current flow is low and nodes of Ranvier are spaced further apart Myelination sheets increase conduction velocity Compound AP = sum of all activated nerves Spike amplitude is proportional to fiber diameter April 15, 2009

Innervations of dorsal roots Dermatomes Important for location of spinal injury

Distinct ascending pathways Dorsal column-medial lemniscal system Touch and proprioception from limbs and trunk Somtatotopically organized from spinal to cortical level Ascends ipsilateral side Cross over to contralateral side in medulla Anterolateral system Spinal lamina I, IV, V, VII, VII Pain and temperature from limbs and trunks Cross over to contralateral side in spinal cord Contralateral April 15, 2009

From Ch. 24 “Principles of Neural Science”, 4th Ed. Kandel et al The perception of pain From Ch. 24 “Principles of Neural Science”, 4th Ed. Kandel et al

Somatic sensations Somatic sensation = bodily sensation Pain is a submodality of somatic sensation Pain and nociception (conscious vs. peripheral) Pain sensation is the most salient sensation Pricking Burning Aching Stinging Soreness Pain is a warning of actual or potential injury and damage Pain depends on the psychological state The same stimulus can result in different responses under similar conditions and in different individuals

Mechanical nociceptor Nociceptors Information about stimuli that can damage tissue are conveyed by nociceptors Chemicals are released from traumatized tissue E.g. Substance P, histamine, and bradykinin 3 classes of nociceptors Mechnical: pinch, punctate, squeeze Thermal: above 45 deg or below 5 deg Polymodal: mechanical, thermal, chemical Mechanical nociceptor April 29, 2009

Somatic receptor types 1 2 3 4 April 29, 2009

Afferent fibers Different size and conduction velocity of axons Large fibers conduct faster than small/ thin fibers because the internal resistance to current flow is low and nodes of Ranvier are spaced further apart Myelination sheets increase conduction velocity Compound AP = sum of all activated nerves Spike amplitude is proportional to fiber diameter April 29, 2009

Nociceptive afferents DRG Spinal dorsal horn Compound Action Potential First pain: Sharp and pricking, faster A-delta fibers Second pain, burning and dull, slower C-fibers Blocking each nerve blocks the sensation April 15, 2009

Spinal dorsal horn neurons 2 overall types of interneurons: Nociceptive specific: responds exclusively to noxious stimuli Wide dynamic range neurons: graded response to non-noxious and noxious stimuli Lamina I and II Direct input from mainly A-delta and C fibers. NS and WDR interneurons Lamina III and IV Direct input from A-beta. Nonnoxious input. Topographically organised receptive field Lamina V Direct input from A-beta and A-delta. Direct/ indirect from C-fibers. Convergence of visceral afferents. WDR interneurons projecting to brain stem and thalamus. Lamina VI Direct input from A-alpha (nonnoxious) from joints and muscle Lamina VII and VIII Respond to noxious input. Polysynaptic. Bilateral response April 29, 2009

Neurotransmitters Fast synaptic potentials Slow synaptic potentials Glutamate (amino acid) Efficient reuptake of amino acids Range: postsynaptic neurons in vicinity Slow synaptic potentials Neuropeptides e.g. Substance P No reuptake mechanisms Range: diffusion, many neurons, unlocalized nature of pain Neuropeptides Released and increased in persistent pain conditions Enhances and prolong the actions of glutamate Application of substance P produces signs of inflammation e.g. heat, redness, and swelling April 29, 2009

Peripheral activation and sensitization April 29, 2009

Chronic pain Chronic pain appears to serve no useful purpose Abnormal pain states Nociceptive and neuropathic Nociceptive pain Direct activation of nociceptors Tissue damage or inflammation Neuropathic pain Direct injury to the nerves Peripheral or central Burning or electrical sensation April 29, 2009

Chronic pain Spontaneous ongoing pain Referred pain Hyperalgesia Pain of variable intensity and duration Spontaneous discharges in periphery and centrally Referred pain Pain in a location distant from the source. Could be explained by viscero-somatic convergence in lamina V Hyperalgesia Increased pain sensitivity Allodynia Non-painful input becomes painful e.g. touch on sun burned skin Allodynia and hyperalgesia only exist during stimulation Alterations in biochemical properties and excitability of dorsal horn neurons can induce spontaneous pain, hyperalgesia and allodynia April 29, 2009

Referred pain Signals from muscles and viscera can be felt as pain elsewhere Example: myocardial infarction and angina can be felt in chest and left arm Mechanism: convergence of afferents muscle/ viscera afferents and somatic afferents. Convergence on the same projection neurons in the dorsal horn The brain cannot tell the difference April 29, 2009

Hyperalgesia Peripheral sensitization: Central sensitization: Increased nociceptor sensitivity Increased spontaneous activity Central sensitization: Hyperexcitability of spinal dorsal horn neurons Wind-up: progressive increased response = amplification (depends on glutamate acting on NMDA receptors) Prolonged after-discharges to afferent input Expansion of peripheral receptive fields of central neurons Can be induced by repetitive firing of nociceptive afferents Primary hyperalgesia Hyperalgesia in damaged area (within 5-10mm) Peripheral sensitization Secondary hyperalgesia: Hyperalgesia in surrounding undamaged tissue (10-20mm). Peripheral and central sensitization April 29, 2009

Clinical hyperalgesia Myofascial pain patients (PTS) vs. normal controls (CTR) Myofascial trigger points are hyperalgesic contractures in the muscle Pressure pain thresholds P<0.001 Niddam et al. 2008 PTS CTR P<0.001 IMES stimulus-response curves April 29, 2009

Pain and the brain Pain is a subjective conscious experience. Pain does not exist without the brain CNS inhibitory or facilitatory mechanisms are remarkable efficient in decreasing or amplifying the pain experience Changes in CNS contributes to chronic pain (reorganization: biochemical, atrophy, functions) A better understanding of endogenous pain modulatory systems may lead to new mechanism-based therapies and drug targets April 29, 2009

Pain and the brain: modulation Factors that can influence the pain experience Top-down brain processes Memories (previous experience) Emotion Cognition (attention/ distraction) Mood (depression, anxiety) Context (stress, anticipation/ expectation, placebo) Endogenous pain control systems Other factors Genes Pathological factors (structure, transmitters, receptors, transporters etc.) Age, gender April 29, 2009

Acute vs. chronic pain Acute pain characteristics Activation of peripheral receptors under normal conditions Sensation of pain closely related to the duration of the stimulus Chronic pain characteristics Spontaneous ongoing pain Peripheral sensitization (spontaneous resting activity and hyperexcitable receptors) Central sensitization (prolonged peripheral input) Lowered pain threshold (Hyperalgesia) Non-nociceptive input becomes painful (allodynia) Functional and structural changes in PNS and CNS Segmental expansion of receptive fields De novo synthesis of membrane proteins Spouting of spinal terminals of afferent fibers Formation of new synaptic contacts Altered balance in descending influences April 29, 2009

Acute vs. chronic pain It is important to differentiate between: Acute and chronic pain states Different time horizons engage different emotional coping strategies Chronic pain becomes maladaptive and is highly co-morbid with mood and anxiety disorders Chronic pain induces CNS changes Ongoing spontaneous chronic pain vs. perturbations of chronic pain (allodynia/ hyperalgesia) Passive vs. active coping => medial vs. lateral brain regions? April 29, 2009

Neuroimaging of acute pain Cutaneous pain Muscle pain Visceral pain Insula Amygdala ACC PCC Vermis Thalamus PPC PFC Chen et al. Tooth pain Lin et al. (preliminary) Lu et al., 2004 Niddam et al., 2002

Distinct ascending pathways Dorsal column-medial lemniscal system Touch and proprioception from limbs and trunk Somtatotopically organized from spinal to cortical level Ascends ipsilateral side Cross over to contralateral side in medulla Spinothalamic pathway Spinal lamina I, V-VII Pain and temperature from limbs and trunks Cross over to contralateral side in spinal cord Contralateral April 29, 2009

Ascending pathways 5 major ascending pathways Thalamic nuclei Spinothalamic: axons of nociceptive specific and WDR neurons from laminae I and V-VII; contralateral projection, ascends in anterolateral white matter Spinoreticular: neurons in laminae VII and VIII; anterolateral ascend Spinomesencephalic: neurons in laminae I and V; anterolateral ascend to PAG, and spinoparabrachial tract to PB, amygdala; pain affect Cervicothalamic: arises from lateral cervical nucleus; laminae III and IV; some projects via the dorsal column to cuneate and gracile nuclei (large fiber pathway) Spinohypothalamic: laminae I, V, VIII; autonomic control Thalamic nuclei Lateral nuclear group: spinothalamic tract, NS and WDR, laminae I and V, small receptive fields, encoding location of injury Medial nuclear group: spinoreticulothalamic tract, laminae VII and VIII April 29, 2009

Ascending pathways April 29, 2009

Pain pathways in the brain Ascending pathways and cortical/ sub-cortical connectivity Spino-bulbo-spinal loop (pain facilitation) Apkarian et al. 2005 Millan 2002 Pain components (variable expression): Sensory-discriminative, affective-motivational Cognitive, Motor April 29, 2009

Pain and the brain: pathways Stress and the reward/ motivation system Dopamine based mesolimbic system modulates mainly tonic pain Hypothalamus Amygdala Hippocampus Ventral tegmental area Dopoaminergic nucleus Ventral striatum/ Nucleus accumbens Ventral pallidum MDm thalamus Pain modulation Anterior cingulate April 29, 2009

Motivation and emotions Borsook 2007, EJP

Pain modulation: large fibers The balance of activity in small- and large-diameter fibers is important in pain transmission/ determines the pain intensity The gate control theory involves 4 types of neurons in the dorsal horn of the spinal cord Large-diameter afferent (non-nociceptive) Small-diameter afferent (nociceptive) Inhibitory interneurons (spontaneously active) Projection neurons Large-diameter fibers Excites interneuron and decrease pain transmission/ Closes the pain-gate Small-diameter fibers Inhibits interneuron and increases pain transmission/ Opens the pain-gate Observation: in absence of conduction in A-ά/ A-β fibers pain perception is abnormal Pin prick, pinch, ice cold produces burning pain The gate control hypothesis April 29, 2009

Pain modulation: opiods Direct stimulation of PAG produces analgesia Inhibits firing of nociceptive neurons in lamina I and V Descending pathway recruited: PAG excites rostroventral medulla/ nucleus raphe magnus (5HT) Moprhine (an opioid) induced analgesia via endogenous opioid receptors in descending pathway Opioid receptors Types: -, δ-, κ-, nociceptin Transmitters: enkephalins, β-endorphin, dynorphin Location (mainly): PAG, ventral medulla, superficial dorsal horn Stress-induced analgesia of escapable pain is mediated via the endogenous opioid system Side effects Other regions not involved in pain also contains opioid receptor Minimize diffusion by local administration can avoid side effects e.g. in cerebrospinal fluid April 29, 2009