OS 202 Human Body and Mind 1: Physiology of Pain and Light Touch Pathways PDF

OS 202: HUMAN BODY AND MIND 1: INTEGRATION AND CONTROL SYSTEMS PHYSIOLOGY OF PAIN AND LIGHT TOUCH UPCM 2029 | Dr. Christian Wilson Turalde | LU3 A.Y. 2024-2025 OUTLINE B.​ ACTION P...

OS 202: HUMAN BODY AND MIND 1: INTEGRATION AND CONTROL SYSTEMS PHYSIOLOGY OF PAIN AND LIGHT TOUCH UPCM 2029 | Dr. Christian Wilson Turalde | LU3 A.Y. 2024-2025 OUTLINE B.​ ACTION POTENTIALS OF SOMATOSENSORY FIBERS I.​ Receptors and Pathways III.​ Pain and Temperature CLASSIFICATION OF SOMATOSENSORY FIBERS A.​ Primary Sensory A.​ Nociception and ​ The first peripheral nerve functional group classification was Neurons Nociceptors devised in 1894 by Charles Sherrington B.​ Action Potentials of B.​ Role of Dorsal Horn in ​ Based on the diameter of myelin-stained axons in sensory nerves Somatosensory Fibers Nociception ​ There is overlap between the fiber subgroups in terms of axonal C.​ Specialized C.​ Hyperalgesia diameters Somatosensory D.​ Cortical Mechanisms in ​ The conduction velocity of myelinated peripheral nerve fibers is a Receptors Nociception function of the nerve fiber diameter D.​ Somatosensory E.​ Nociceptive Pathways ○​ The larger the diameter the higher the conduction velocity Pathways F.​ Opioids and Table 1. NERVE I, II, III, IV CLASSIFICATION OF FIBERS E.​ Thalamus Endogenous Pain II.​ Touch Control FIBER CONDUCTION MUSCLE CUTANEOU A.​ Mechanoreceptors IV.​ References DIAMETER VELOCITY NERVE S NERVE B.​ Somatosensory Cortex (µm) (m/s) C.​ Specific Lesions Myelinated LEARNING OBJECTIVES Large diameter I Aα 12-20 72-120 1.​ Discuss the components of the somatosensory system from Medium receptors to cortex. II Aβ 6-12 36-72 diameter 2.​Correlate the structures with the functions of various sensory receptors. Small diameter III Aδ 1-6 4-36 3.​Elucidate the various mechanisms of signal transduction from Unmyelinated IV C 0.2-1.5 0.4-2.0 sensors to the cortex. 4.​Discuss the mechanisms of nociception and pain control. *Memorization tip: Fiber diameters and conduction velocities are multiples of 6 (1-6, 6-12, 12- roughly 20) I.​ RECEPTORS AND PATHWAYS A.​ PRIMARY SENSORY NEURONS ​ Primary neurons of the somatosensory system are clustered in the dorsal root ganglia (DRG) ○​ DRG is a pseudounipolar neuron ​ Has a receiving branch where the sensory receptor is found ​ Has a sending-off branch facilitating the ascending transmission to the spinal cord and the higher centers above it ○​ Adjacent to the spinal nerve roots ​ Their axons have two branches: ○​ One projecting to the periphery ○​ One projecting to the spinal cord or brain stem (afferent signal processing) Figure 1. Diagram of primary sensory neurons highlighting the DRG. Figure 3. Axon diameters and conduction velocities. STRUCTURE OF A PERIPHERAL NERVE ​ Nerve fibers are organized in nerves with 3 layers of connective CONDUCTION VELOCITIES OF PERIPHERAL NERVES tissue: ​ Which among the choices has the fastest velocity? Answer: Large ○​ Endoneurium - surrounds each individual nerve fiber diameter ○​ Perineurium - surrounds the fascicles ​ Some fibers are located between Aα and Aβ. ○​ Epineurium - surrounds several groups of fascicles; covers ​ Large fiber diameters are the first to be stimulated. ​ When we dissect a median nerve, it is wrong to say that we already ○​ If you have a very perceptible stimulus, only Aα is activated. see the myelin sheath because it is a histological structure inside ○​ The next larger fiber is stimulated if you record the action the endoneurium. potential using a microelectrode and increase the stimulus. ​ The surface of the median nerve after being dissected is the ○​ Another strong stimulus will eventually recruit Aδ fibers. epineurium. ​ Inside the epineurium, there are bundles of fascicles called perineurium. For memorization: ○​ Perineurium = Pasicle (fascicle) ○​ Indoneurium (endoneurium) = Individual nerve fibers Figure 4. Nerve response, stimulus intensity, and sensations evoked by the different fibers. C.​ SPECIALIZED SOMATOSENSORY RECEPTORS CLASSIFICATION OF SOMATIC SENSATION ​ Somatosensory system employs several types of receptors ○​ Cutaneous and subcutaneous mechanoreceptors ○​ Thermal receptors ○​ Nocireceptors ○​ Muscle and skeletal receptors ​ The particular receptor class in the the nerve terminal of a sensory neuron determines the type of stimulus detected by the neuron Figure 2. Ultrastructure of a peripheral nerve. Trans 06 TG2: Alfaro, Alog, Ambil, Amigable, Andonaque, Ang, Angulo, Aningga TH: Ong 1 of 10 Table 2. Somatosensory system’s receptor types and their corresponding of stimuli fiber groups ○​ Rapidly adapting receptors are activated when they receive a stimulus but they lose the activation after a while even if the Receptor Type Fiber Group stimulus is still present Cutaneous and subcutaneous mechanoreceptors ​ e.g. wearing clothes - an individual does not feel every square millimeter of fabric on their skin throughout day Meissner corpuscle Aɑ, β ○​ Slowly adapting receptors do NOT lose their activation (firing Merkel disk receptor Aɑ, β rate) as long as the stimulation is present Pacinian corpuscle Aɑ, β Ruffini ending Aɑ, β Hairy-tylotrich, hair-guard Aɑ, β Hair-down Aɑ Field Aɑ, β C mechanoreceptor C Thermal receptors Cool receptors Aδ Warm receptors C Heat receptors Aδ Cold receptors C Nocireceptors Mechanical Aδ Thermal-mechanical (heat) Aδ Thermal-mechanical (cold) C Figure 6. Four types of mechanoreceptors Polymodal C For memorization from Doc Turalde: Muscle and skeletal receptors ​ List down the 4 types alphabetically (i.e., Meissner → Merkel → Muscle spindle primary Aɑ Pacinian → Ruffini) ​ Assign alternating “R” (rapidly adapting) or “S” (slowly adapting) Muscle spindle secondary Aβ for each mechanoreceptor Golgi tendon organ Aɑ ​ The Meissner corpuscle and Merkel cells are categorized as “1” (superficial structures); Pacinian corpuscle and Ruffini endings Joint capsule receptors Aβ are classified as “2” (deep structures) Stretch-sensitive free endings Aδ Mechanoreceptors for Proprioception Complete table in appendix ​ Muscle spindle: principal receptor mediating proprioception MECHANORECEPTORS FOR TOUCH AND PROPRIOCEPTION ​ Located within skeletal muscle and excited by stretch of the muscle ​ Ion channels in mechanoreceptor nerve terminals are activated by ○​ Directly activated by forces conveyed through lipid tension mechanical stimuli that stretch or deform the cell membrane: ​ When the muscle is stretched, there is a conformational ○​ Directly activated by forces conveyed through lipid tension change in the lipid bilayer ○​ Conveyed through structural proteins linked to the ion ​ This is detected by the brain under the opening of the ion channels channels ○​ Indirectly activated by forces conveyed to a force sensor (a ​ The opening of ion channels depolarizes the cells and separate protein) transmits the sensory signals Figure 7. Parts of the muscle spindle THERMAL RECEPTORS ​ Four distinct types of thermal sensation that humans recognize: cold, cool warm, and hot ​ 32°C - peripheral, neutral temperature ○​ beginning at 10° to 15°C (50-59°F) → pain ○​ Below 31°C (88°F) → cold ○​ 31° to 32°C → cool ○​ 32° to 36°C → warm ○​ Above 36°C (97°F) → hot ○​ beginning 45°C (113°F) → pain Figure 5. Mechanical stimuli that can affect the cell membrane Table 3. TRP ion channels [Batch 2028 Trans] 4 Types of Mechanoreceptors for Touch TRP ion Nomenclature Activators ​ Touch is mediated by four types of mechanoreceptors channels ○​ Meissner corpuscle (RA1) Temperature: cool/cold ​ RA1 - rapidly adapting and superficial TRPA1 Ankyrin 1 Co-activator: garlic ○​ Merkel cells (SA1) Example: applying garlic on wounds ​ SA1 - slowly adapting and superficial ○​ Pacinian corpuscle (RA2) Temperature: cool/cold ​ RA2 - rapidly adapting and deep TRPM8 Melastatin 8 Co-activator: menthol ○​ Ruffini endings (SA2) Example: toothpaste ​ SA1 - slowly adapting and deep Temperature: 32°C, perceive the ​ The receptive field of a mechanoreceptor reflects the location and TRPV4 Vanilloid 4 normal temperature (Figure 8) distribution of its terminal in the skin. ​ Rapid and slow adapting receptors react differently in the presence TRPV3 Vanilloid 3 Temperature: warm/hot OS 202 Physiology of Pain and Light Touch Pathways 2 of 10  Co-activator: camphor ASCENDING PATHWAYS Example: Efficascent oil Somatosensory System Temperature: warm/hot TRPV1 Vanilloid 1 ​ Includes dorsal column and anterolateral pathways Co-activator: pepper ​ It gives clues to identify the area of localization Temperature: warm/hot TRPV2 Vanilloid 2 Co-activator: candlelight Figure 8. TRP ion channels PRURITUS/ITCH ​ Unpleasant sensory experience confined to the skin, ocular conjunctiva, and mucosa ​ Induced by the injection of histamine or procedures that release endogenous histamine ​ Mediated by C fibers with very slow conduction velocities (0.5 m/s) ​ Transmission of pruritogen ○​ Pruritogen (stimulus that activates pruritic receptors) → dorsal root ganglia → higher centers → interpreted as itch ​ Scratching mechanism ○​ Scratch → elicit pain → transmitted to the dorsal root ganglion → Figure 11. Dorsal Column and Anterolateral Pathways. activate inhibitory interneuron → release GABA → pruritic transmission is inhibited (reason why scratching is comfortable) Dorsal Column-Medial Lemniscus Pathway ​ Transmits vibration and position sense ○​ Large diameter fibers ​ Decussate at medulla ​ Pathway (Figure ): Light touch 1. Touch activates receptors in the fingertips 2. Impulses are received by the first-order neurons of the dorsal root ganglion 3. Signals from the first-order neurons are transmitted to the fasciculus gracilis and fasciculus cuneatus of the dorsal column of the spinal cord ○​ Fasciculus - collection of axonal fibers 4. First-order neurons synapse with the second-order neurons found in the nucleus gracilis and nucleus cuneatus in the medulla ○​ Nucleus - collection of neuronal cell bodies 5. Second-order neurons cross to the contralateral side 6. Ascend to the central nervous system via the medial lemniscus pathway 7. Medial lemniscus terminates to the third-order neurons in the ventroposterolateral (VPL) or ventroposteromedial (VPM) of the thalamus Figure 9. Transmission of pruritogen 8. Information is transmitted from the thalamus to the somesthetic area in the cortex D.​ SOMATOSENSORY PATHWAYS ​ As fibers approach the spinal cord, they separate into medial and For memorization: lateral divisions ○​ VPL - Limbs ​ Rexed laminae is found in the dorsal horn of the gray matter of the ○​ VPM - Mukha spinal cord ○​ Anterolateral Pathway - decussation at the spinal cord ○​ Medial division ○​ Dorsal Column-Medial Lemniscus Pathway - decussation at the ​ Aα & Aβ fibers medulla ​ Transmit proprioceptive and cutaneous information ​ Transmitted in Rexed lamina IV and V (mechanoreceptors Anterolateral Pathway found here) ​ Transmits pain and temperature ○​ Lateral division ○​ Small, unmyelinated fibers ​ Aδ & C fibers ​ White fiber tract is found at the anterolateral system of the spinal ​ Transmit noxious, thermal, and visceral information cord ​ Transmitted in Rexed lamina I and II ​ Decussate at the spinal cord → ○​ One to two levels up or below the particular entry point of the nerve fiber ​ Pathway (Figure ): Pain ○​ Pain stimulus → first-order neuron of the dorsal root ganglion cell → second-order neuron in the Rexed lamina of the spinal cord → cross to the contralateral side → brainstem → VPL or VPM of the thalamus → somesthetic area in the cortex E.​ THALAMUS ROLE OF THALAMUS IN THE SS SYSTEM ​ Important subthalamic nuclei in the thalamus ○​ Ventral Posterior Nucleus (VPN) ​ Relays tactile and proprioceptive information ​ Ventral Posterolateral Nucleus (VPL) ​ Ventral Posteromedial Nucleus (VPM) Figure 10. Rexed laminae. OS 202 Physiology of Pain and Light Touch Pathways 3 of 10  Figure 16. Frontal lobe ​ Divided by: ○​ Pre-central sulcus ○​ Superior Frontal sulcus ○​ Inferior Frontal sulcus ○​ Anterior Ascending ramus ​ Sub-lobes: Figure 12. Overview of the thalamic nuclei ○​ Pre-central Gyrus ○​ Superior Frontal Gyrus THE BRAIN ○​ Middle Frontal Gyrus ​ An organ inside the skull that consists of: ○​ Inferior Frontal Gyrus ○​ Cerebral Hemispheres ​ On nomenclature ○​ Brainstem ○​ These nomenclatures are systems for the anatomist ○​ Cerebellum ​ They are labelling the lobules or sub-lobes into anatomic structures ○​ Physiologists would name these structures differently as Primary Motor Area and the Association Motor Areas ​ Brodmann Classification can also be used ​Neurohistological system of nomenclature Temporal Lobe Figure 13. Components of the brain External Topography of the Brain Figure 17. Temporal lobe ​ Divided by: ○​ Lateral Sylvian Fissure ○​ Superior Temporal Sulcus ○​ Middle Temporal Sulcus Parietal Lobe Figure 14. External topography of the brain ​ Gyrus - ridge ​ Sulcus - indentations ○​ Central Sulcus of Rolando ​ Separates frontal and parietal lobes ​Anterior: frontal lobe Figure 18. Parietal lobe ​Posterior: parietal lobe ​ Divided by: ​ Fissure - deeper indentations ○​ Post-central sulcus ○​ Lateral Sylvian Fissure ○​ Intra-parietal sulcus ​ Separates temporal lobe from the other lobes ​ Upon retraction of the lateral sylvian fissure, the Island Reil Somatosensory Cortex (or Insular cortex) can be seen Memorization tip from Doc Turalde: ○​ Si Rolando nakatayo, si Sylvia nakahiga :o Figure 19. Somatosensory cortex ​ Primary Somatosensory Cortex ○​ Located in the parietal lobe ○​ Nomenclature ​ In neurophysiologic terms, this is called the Primary Figure 15. Island of Reil Somatosensory Cortex or S-1 ​ In neuroanatomical terms, this is called the Postcentral Gyrus Frontal Lobe ​ In Brodmann classification, this is called the Brodmann Area 3, 1, 2 ​In neurophysiological perspective, the signal comes from3 first before sending to 1 then 2 ​ Secondary Somatosensory Cortex ○​ Located in the parietal operculum ​ Parts of the body served by the somatosensory cortex (similar to motor homunculus) OS 202 Physiology of Pain and Light Touch Pathways 4 of 10  ○​ Face ○​ ~2mm on the fingers ​ Served by the lateral aspect ○​ 10 mm on the palm ○​ Arms ○​ 40 mm on the arm, thigh and back ○​ Trunk Spatial Acuity: Neurophysiological Basis for Braille ○​ Lower extremities ​ Tactile acuity threshold ​ Served by the median aspect ○​ The groove, width, ridge width, or font size that yields 75% ​ Commensurate to the amount of stimulus being represented correct performance (detectable midway between chance and ○​ Bigger representation for the face because it is more sensitive perfect accuracy) ○​ More neurons are dedicated to the more important aspects ○​ The threshold in the fingertip is 1.0 mm in each of these tests (evolutionary trait) ​ The two-point threshold also serves as the neurophysiological basis for braille in that the font is not made arbitrarily ○​ There is a minimum font size and distance between the dots to make sure it is still accurately perceivable ​ The Figure below shows the action potentials detected by each of the isolated mechanoreceptors showing the ability of the superficial receptors to differentiate and detect distinctly as compared to the deeper mechanoreceptors Figure 20. Homunculi of the motor cortex and sensory cortex of the human brain II.​ TOUCH A.​ MECHANORECEPTORS ​ There are 4 mechanoreceptors responsible for the sense of touch and they are classified into two types: ○​ Type I (Superficial): Meissner corpuscles & Merkel cells ○​ Type II (Those found in the dermis/deep): Pacinian & Ruffini Figure 22. Action potential graph of mechanoreceptors when reading braille corpuscles Role of Mechanoreceptors on Grip ​ They are further classified into slow adapting (SA) and rapidly adapting (RA) (i.e. rapidly adapting type I mechanoreceptors are labeled RA1) Table 4. Classifications of the Different Mechanoreceptors Type I Type II SA1 RA1 SA1 RA2 Subtype Merkel Meissner Ruffini Pacinian Receptor cells corpuscles Ending corpuscles Best edges, skin lateralization vibration stimulus points stretch Response to sustained sustained sustained with slow none with slow none adaptation adaptation adaptation RECEPTIVE FIELDS ​ there are specific areas of the skin from which individual mechanoreceptor fibers convey information (Refer to Figure below) ​ the receptive fields of Type I mechanoreceptors are more distinct Figure 23. Neural responses of the mechanoreceptors on grip. ○​ they are small, highly localized fields with multiple spots of high ​ The graph in the Figure above shows how the different receptors sensitivity are activated when picking up and carrying a bag: ​ In contrast, Type II mechanoreceptors have a broad and ○​ When you first hold the bag, the superficial receptors activate non-distinct perceptive field first, but the rapidly adapting Meissner corpuscles should ○​ they collect information from a broader area of skin eventually make you feel like you are not holding the bag ○​ contains a single “hot spot” where sensitivity to touch is greatest ​ The slow adapting Merkel cells, however are still receptive to the touch stimulus ○​ Deep sensations are only fired when the bag is already being carried and there is elevation ​ The rapidly adapting Pacinian corpuscles however will only activate at the moment of lifting the bag and releasing it B.​ SOMATOSENSORY CORTEX HIERARCHICAL CONNECTIONS BETWEEN SS CORTICES ​ Neurons projecting from the thalamus send their axons mainly to areas 3a and 3b ○​ Some thalamic neurons also project to areas 1 and 2 ​ Neurons in cortical areas 3a and 3b project to areas 1 and 2 ​ Information from S-I is conveyed to S-II and 5 Figure 21. Receptive fields of the different mechanoreceptors CLINICAL APPLICATIONS Two-Point Threshold ​ It measures the minimum distance at which two stimuli are resolved as distinct ○​ i.e. the minimum distance at which two safety pins pricked onto your skin can still be felt as two distinct pricks instead of just one ​ The receptive fields of the mechanoreceptors serve as a basis for this concept ​ This distance varies for different body regions: Figure 24. Cortical representation of somatosensory fibers. OS 202 Physiology of Pain and Light Touch Pathways 5 of 10 ​ Note the order of 3-1-2. ​ From the thalamus, most of the signals (e.g.ventroposterolateral and ventroposteromedial) will be received by 3a and 3b. ​ The signals are then transmitted to the supplementary Brodmann area. ​ Certain parts of the somatosensory cortex have preferred mechanoreceptors. RECEPTIVE FIELDS IN NEURONS AND THE SS CORTEX ​ This sagittal section (in Figure 25) illustrates the rostrocaudal anatomy of the four regions of S-I (areas 3a, 3b, 1, and 2) as well as the primary motor cortex (area 4) and the posterior parietal cortex (area 5). ○​ The four regions process different types of somatosensory information. ○​ Certain parts of the somatosensory cortex have preferred mechanoreceptors. ​ e.g. 3a for muscle spindles, 3b for SA1 and RA1 receptors, etc. Figure 27. Functional MRI showing the brain activity during active vs. passive touch C.​ SPECIFIC LESIONS ​ Damage in the somatosensory cortex will also manifest as motor problems. Figure 25. Sagittal section of the rostrocaudal anatomy of S-I. COLUMNAR ORGANIZATION OF THE SOMATOSENSORY CORTEX ​ The somatosensory inputs from specific parts of the human body are organized in columnar arrangement from the cortical surface to the white matter. Figure 28. Tactile deficits caused by lesions in different somatosensory areas ​ When there are anterior or posterior parietal lesions, motor performance will be negatively affected. ○​ In the graph, the motor performance of the apes in the experiment failed to reach the normal performance range. ○​ Damage in the somatosensory cortex will be demonstrated by motor dysfunction. ​ The motor system also needs to feel how the limb moves for effective movements to ensue. Clinical Application ​ Cortical disruption of somatosensory system impairs coordinated motor response. ○​ e.g. Finger coordination is disrupted when synaptic transmission in the somatic sensory cortex is inhibited in a monkey Figure 26. Columnar organization of the somatosensory cortex (enlarged in Appendix) ​ Fibers from the thalamus are mostly received by the fourth layer. Clinical Application ​ Active touch evokes more complex responses in somatosensory cortices than passive touch. ○​ When looking for things in a bag, we tend to rummage around the bag actively instead of passively placing a hand inside the bag. Figure 29. Result of muscimol on finger coordination of a monkey ​ A monkey with damage on one side of the brain can still grasp the grape in a funnel using the ipsilateral hand. However, motor dysfunction can already be observed on the contralateral side, even when the problem is somatosensory. OS 202 Physiology of Pain and Light Touch Pathways 6 of 10  III.​ PAIN AND TEMPERATURE A.​ NOCICEPTORS AND NOCICEPTION DORSAL HORN ​ The cell bodies of primary nociceptive neurons are located in the dorsal root ganglia or trigeminal nucleus ​ Most fibers from DRG terminate in the neurons of the dorsal horn in a very organized manner. ○​ Nociception-Specific neurons are located in Rexed lamina I or Marginal Layer Figure 32. Cascade of secretions causing hyperalgesia D.​ NOCICEPTIVE PATHWAYS ASCENDING PATHWAYS OF NOCICEPTION ​ The ascending pathways of nociception are the following: ○​ Spinothalamic tract ○​ Spinoreticular tract ○​ Spinomesencephalic tract Figure 30. Organization of neurons in the dorsal horn ​ Recall: These ascending spinal cord tracts are part of the REFERRED PAIN anterolateral system together with the spinotectal tract and the spinohypothalamic tract. ​ Due to the convergence of visceral and somatic afferent fibers to a single DRG ○​ Organs develop with cutaneous anatomy ​ The brain has no way of knowing if the noxious stimuli is coming from the skin or from the visceral organ ​ Examples ○​ Left shoulder pain in the case of a heart attack ○​ McBurney’s Point: location on the abdomen where tenderness is most painful with appendicitis Figure 33. Ascending pathways for nociception (see Appendix) Table 5. Ascending pathways for nociception Location in Tract Decussation Function Cord Spinothalamic Anterior Lateral, Crude touch, tract commissure anterior Pain, columns Temperature Spinoreticular Mostly Lateral Behavioral tract uncrossed column response to Figure 31. Convergence of neurons in visceral organs and skin pain, Arousal B.​ NEUROTRANSMITTERS MEDIATING PAIN ​ Glutamate is the primary neurotransmitter regardless of modality Spinomesen- Anterior Lateral Central ​ Neuropeptides: co-transmitters released by nociceptors cephalic commissure column modulation of ○​ Substance P tract pain ○​ Calcitonin Gene Related Peptide (CGRP) ​ CGRP inhibitors are administered as medication for migraines THE GATE-CONTROL THEORY OF NOCICEPTION ○​ Somatostatin ​ This theory suggests that before the sensation of pain is sent to the ○​ Galanin central nervous system, a "gatelike" mechanism in the dorsal ​ C fibers contain 2 different types of secretory vesicles horn in the spinal cord modulates several neural impulses from ○​ Small and clear: glutamate the peripheral nervous system that may indicate pain. ○​ Large and dense: Substance P ​ It also suggests that low-threshold fiber activation can C.​ HYPERALGESIA attenuate pain, accounting for observations such as why massage or rubbing an injury can reduce the perception of pain. ​ An increase in sensitivity to pain elicited by sensitizing peripheral ​ Transmission of pain signal: nociceptors through repetitive exposure to noxious stimuli ○​ C fibers, a type of primary afferent neuron, transmit pain signals ​ Triggered by a complex mix of chemicals released from damaged to the projection neurons, a type of second-order neuron. cells that are at the site of tissue injury ○​ These pain signals can be inhibited by stimulating the adjacent ​ Mechanism of neurogenic inflammation Aβ fibers. ○​ Bradykinin stimulates nociceptors ○​ Aβ fibers then send a positive signal to inhibitory neurons. ○​ Nociceptors release Substance P and CGRP ○​ The inhibitory interneurons block the pain signal from being ○​ Substance P stimulates a mast cell response transmitted through the projection neurons to the brain, thus ​ Degranulation and release of histamine decreasing the perception of pain. ​ Direct excitation of the nociceptor ○​ CGRP dilates the blood vessels ​ Causes edema ​ Liberates more bradykinin, and the cycle continues OS 202 Physiology of Pain and Light Touch Pathways 7 of 10  Figure 34. The Gate-Control Theory of Nociception DESCENDING MONOAMINERGIC PATHWAYS ​ These are named monoaminergic because they use monoamines. Figure 36. Representation of the dorsal horn and Rexed lamina 1 and 2 ​ Serotonergic pathway ○​ Uses serotonin ○​ Nucleus raphe magnus → dorsolateral funiculus → dorsal horn of the spinal cord ​ Noradrenergic system ○​ Uses norepinephrine ○​ Locus ceruleus and other nuclei in the pons and medulla ○​ The excess norepinephrine produced by locus ceruleus go down the descending pathway, inhibiting pain sensation. ​ This is the reason why adrenaline rush lessens pain perception. ​ These pathways modulate pain sensation, an evolutionary adaptation that allows us to function even when in pain. ○​ This is done by inhibiting nociceptive projection neurons through direct connections as well as through interneurons in the superficial layers of the dorsal horn. Figure 37. Interneurons from the descending pathway ​ By virtue of the descending mechanism, there are extra fibers from above ​ The norepinephrine and serotonin fibers will stimulate an inhibitory interneuron, thereby inhibiting the painful transmission →​This is the reason why it is helpful to use Sumatriptan, serotonin agonist for patients with migraine →​Antidepressants are used for patients with chronic neuropathic pain because they are serotonin reuptake inhibitors ​ When there are high levels of serotonin (the happy hormone), the painful sensation is low →​Generally happy people are not that sensitive to pain. E.​ ENDOGENOUS OPIOID PEPTIDES AND RECEPTORS ​ Opioid peptides function as natural painkillers within the body. They bind to opioid receptors located throughout the nervous system, primarily in the brain and spinal cord. ​ These peptides include endorphins, enkephalins, and dynorphins. ​ The four major classes of opioid receptors include ○​ Mu (μ) - sensitive to endorphins ○​ Delta (δ) - sensitive to enkephalins ○​ Kappa (κ) - sensitive to dynorphins ○​ Orphanin FQ Table 6. Endogenous Opioid Peptides and Receptors Propeptide Peptide Preferential receptor POMC β-endorphin μ/δ Endomorphin-1 μ Endomorphin-2 μ Proenkephalin Met-enkephalin δ Figure 35. Descending monoaminergic pathways THE GATE-CONTROL THEORY OF NOCICEPTION Leu-enkephalin δ Information from 2028 Trans Prodynorphin Dynorphin A κ ​ In Rexed lamina 1 and 2 of the dorsal horn, transmission of pain occurs to the second-order neurons of the nociceptor fibers Dynorphin B κ Pro-orphanin FQ Orphanin FQ Orphan receptor OS 202 Physiology of Pain and Light Touch Pathways 8 of 10  F.​ SAMPLE QUESTIONS d.​ Ventro-posterior nucleus TOUCH RECEPTORS AND PATHWAYS 1. Which of the following cutaneous mechanoreceptor responds best 1. Which class of sensory nerve fibers has a diameter of 6-12 um? to vibration stimulus? a.​ alpha a.​ Meissner Corpuscle b.​ A beta b.​ Merkel Cell c.​ A gamma c.​ Pacinian Corpuscle d.​ C d.​ Ruffini Ending 2. Which of the following classes of nerve fibers have the slowest 2. Which of the following Brodmann area is not part of the primary conduction velocity? somatosensory cortex? a.​ alpha a.​ 1 b.​ A beta b.​ 2 c.​ A gamma c.​ 3 d.​ C d.​ 5 3. Which of the following is a superficial mechanoreceptor that is 3. Active touch stimulus is processed in which Brodmann area within rapidly adapting? the somatosensory cortex? a.​ Meissner Corpuscle a.​ 1 b.​ Merkel Cell b.​ 2 c.​ Pacinian Corpuscle c.​ 3 d.​ Ruffini Ending d.​ 5 4. Which of the following temperature receptor protein (TRP) responds to menthol? PAIN AND TEMPERATURE a.​ TRPA1 1. Which of the following neuropeptides prefers to react with the mu b.​ TRPM8 receptor? c.​ TRPV4 a.​ Dynorphin d.​ TRPV1 b.​ Endorphin 5. Which nucleus of the thalamus receives the general somatosensory c.​ Enkephalin signal from the body? d.​ Orphanin a.​ Anterior nucleus b.​ Dorsomedial nucleus c.​ Pulvinar OS 202 Physiology of Pain and Light Touch Pathways 9 of 10  APPENDIX Specialized Somatosensory Receptors and their fiber group, name and modality Columnar organization of the somatosensory cortex OS 202 Physiology of Pain and Light Touch Pathways 10 of 10