2024 Furstein Pain I-1 PDF

Pathophysiology of Pain Jamie Furstein, PhD, DNAP, CRNA, CPNP-AC, FAANA Definition of Pain International Association for the Study of Pain: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage Most...

Pathophysiology of Pain Jamie Furstein, PhD, DNAP, CRNA, CPNP-AC, FAANA Definition of Pain International Association for the Study of Pain: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage Most common symptom that brings patients to see a physician Furstein DNAP 737 2024 Purpose of Pain Protective in nature Withdrawal from heat source Limit damage joint to prevent further injury Leads to learned behaviors Avoidance Behaviors can become dysfunctional Furstein DNAP 737 2024 Furstein DNAP 737 2024 Goal for today: Walk away with an understanding of the anatomy & physiology of pain Furstein DNAP 737 2024 Anatomy of Pain The somatic senses are the nervous mechanisms that collect sensory information from all over the body The somatosensory system provides information about: Touch Proprioception Temperature Pain Itching Furstein DNAP 737 2024 Anatomy of Pain Somatosensory System Peripheral Nervous Spinal Cord Brain System Ascending & Afferent neurons, Somatosensory descending A-delta & C fibers cortex, thalamus pathways Furstein DNAP 737 2024 Anatomy of Pain Somatosensory System Peripheral Nervous Spinal Cord Brain System Ascending & Afferent neurons, Somatosensory descending A-delta & C fibers cortex, thalamus pathways Furstein DNAP 737 2024 Think BIG, start small… Information Painful sent to the Reaction stimulus brain Furstein DNAP 737 2024 First-Order Neurons Cell body located in the dorsal root ganglion and lies in the vertebral foramina at each spinal cord level Each neuron has a single axon that bifurcates One end travels distal to the periphery Other end travels into the dorsal horn of the spinal cord Furstein DNAP 737 2024 First-Order Neurons Furstein DNAP 737 2024 Axons The neuronal process that carries the action potential from the nerve cell body to a target. In regard to the somatosensory system, primarily concerned with 3 fibers: A-beta fibers A-delta fibers C fibers May or may not be myelinated, which impacts speed of signal transmission Furstein DNAP 737 2024 Axons Furstein DNAP 737 2024 Furstein DNAP 737 2024 Somatic Sensory Receptors Diverse in composition Free nerve endings in the skin Specialized nerve endings (act as amplifiers or filters) Sensory terminals associated with specialized transducing cells that influence the ending by virtue of synapse-like contacts Furstein DNAP 737 2024 Somatic Sensory Receptors All somatic sensory receptors fundamentally work the same way: Stimuli applied to the skin deforms or otherwise changes the nerve ending, which in turn affects the ionic permeability of the receptor membrane The resulting change in permeability generates a depolarizing current, thereby triggering action potentials Furstein DNAP 737 2024 Somatic Sensory Receptors Based on function, three types of cutaneous receptors thought to exist: 1. Mechanoreceptors 2. Thermoreceptors 3. Nociceptors Based on morphology, the receptors near the body surface can be divided into: 1. Free 2. Encapsulated Furstein DNAP 737 2024 Mechanoreceptors Respond to tactile non-painful stimuli Provide information regarding: Touch Pressure Vibration Tickle Position senses (static position & rate of movement) Furstein DNAP 737 2024 Mechanoreceptors Divided into two functional groups based on their response during stimulation: Rapidly adapting respond at the onset/offset of the stimulus Slow adapting respond throughout the duration of the stimulus Four major types of mechanoreceptors: 1. Meissner’s corpuscles 2. Pacinian corpuscles 3. Merkel’s disks 4. Ruffini’s corpuscles Furstein DNAP 737 2024 Mechanoreceptors Divided into two functional groups based on their response during stimulation: Rapidly adapting respond at the onset/offset of the stimulus Slow adapting respond throughout the duration of the stimulus Four major types of mechanoreceptors: 1. Meissner’s corpuscles Rapid 2. Pacinian corpuscles Rapid 3. Merkel’s disks Slow 4. Ruffini’s corpuscles Slow Furstein DNAP 737 2024 Thermoreceptors Function to detect changes in temperature using two types of receptor cells: Warm: sense temps b/t 30-45oC Cold: sense temps b/t 17-27oC Poor indicators of absolute temperature Sense of temperature comes from the comparison of signals from the two types of receptors Furstein DNAP 737 2024 Nociceptors Relatively unspecialized nerve cells with “free endings” that initiate the sensation of pain Conduction along the axons relatively slow compared to that of the mechanoreceptors Split into two pathways: Fast pain: A-delta fibers Slow pain: C fibers Furstein DNAP 737 2024 Nociceptors Present in both somatic & visceral tissues Somatic nociceptors: cutaneous & deep tissue Visceral nociceptors: those in the internal organs Three major classes of nociceptors: A-delta mechanosensitive nociceptors A-delta mechanothermal nociceptors Polymodal nociceptors Furstein DNAP 737 2024 Somatic Sensory Receptors Receptor Type Location Function Associated Axon Meissner’s corpuscles Principally glabrous skin Touch & vibration A-beta fibers Pacinian corpuscles Subcutaneous tissue, Vibration A-beta fibers interosseous membranes, viscera Merkel’s disks All skin, hair follicles Determine continuous touch of A-beta fibers objects against the skin Ruffini’s corpuscles All skin Signal continuous heavy touch A-beta fibers and pressure Thermoreceptors Skin Temperature A-delta fibers (cold receptors) C fibers (warmth receptors) Free nerve endings Skin, organs Pain, itch, touch, pressure A-delta fibers, C fibers Furstein DNAP 737 2024 Somatic Sensory Receptors Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Cutaneous and Subcutaneous Somatic Sensory Receptors. Available from: http://www.ncbi.nlm.nih.gov/books/NBK11162/ Furstein DNAP 737 2024 Quick Review: First-Order Neurons Primary afferent neurons located in the dorsal (sensory) root ganglia in the vertebral foramina at each spinal cord level Each neuron has a single axon that bifurcates One end goes to peripheral tissues One end goes to the dorsal horn of the spinal cord Three types of cutaneous receptors: 1. ________________ 2. ________________ 3. ________________ Furstein DNAP 737 2024 Quick Review: First-Order Neurons Primary afferent neurons located in the dorsal (sensory) root ganglia in the vertebral foramina at each spinal cord level Each neuron has a single axon that bifurcates One end goes to peripheral tissues One end goes to the dorsal horn of the spinal cord Three types of cutaneous receptors: 1. Mechanoreceptors 2. Thermoreceptors 3. Nociceptors Furstein DNAP 737 2024 Quick Review: First-Order Neurons Four major types of mechanoreceptors: 1. _________________ 2. _________________ 3. _________________ 4. _________________ Two types of thermoreceptors: 1. _________ 2. _________ Three major classes of nociceptors: 1. _______________________________ 2. _______________________________ 3. _______________________________ Furstein DNAP 737 2024 Test Your Knowledge ____________ are the cutaneous somatic sensory receptors primarily associated with vibration (pick all that apply): A. Merkel’s disks B. Meissner’s corpuscles C. Ruffini’s corpuscles D. Pacinian corpuscles Furstein DNAP 737 2024 Think BIG, start small… Information Painful sent to the Reaction stimulus brain Furstein DNAP 737 2024 Spinal Cord Anatomy Gray matter Dorsal horn (sensory) Tract of Lissauer Rexed’s laminae Ventral horn (motor) Lateral (autonomic) White matter Central canal Furstein DNAP 737 2024 Rexed’s Laminae Lamina I Marginal layer Receives noxious stimuli from cutaneous and deep somatic tissues via both A-delta & C fibers fibers Relays pain, temperature Axons contribute to the lateral spinothalamic tract Lamina II Substantia gelatinosa of Rolando (sometime reported as laminae II/III) Receives noxious stimuli from C fibers and A-delta fibers to a lesser degree Relays pain, temperature, and mechanical (light touch) information Considered major site of action for opioids Plays a major role in processing and modulating nociceptive sensory input Furstein DNAP 737 2024 Rexed’s Laminae Lamina III/IV Nucleus proprius (sometimes reported as III/IV/V) Receives input from A-beta and A-delta fibers Relays proprioception, mechanical, pain, and temperature sensations First synapse in the spinothalamic tracts occur here Axons contribute to ventral and lateral spinothalamic tracts Lamina V WDR neurons most abundant here Receives noxious and non-noxious, somatic and visceral stimuli from A-delta fibers and to a lesser extent C fibers The convergence of noxious and non-noxious stimuli is manifested clinically as referred pain Furstein DNAP 737 2024 Rexed’s Laminae Furstein DNAP 737 2024 First-Order Neuron Paths Furstein DNAP 737 2024 Ascending Pathways Furstein DNAP 737 2024 Tract of Lissauer Axons penetrating the dorsal horn branch into ascending and descending collaterals forming the Tract of Lissauer Furstein DNAP 737 2024 Spinothalamic Tract On entering the spinal cord, pain fibers terminate on relay neurons in the dorsal horn Signal decussates at the level of the spinal cord Pain signals then take one of two routes to the brain via spinothalamic (anterolateral) pathway Neospinothalamic tract Paleospinothlamic tract Within the spinothalamic tract fibers are arranged topographically Fibers crossing at any level join the deep aspect of the tract formed by those that previously crossed into the tract Fibers relating to the upper limb lie deep Fibers relating to the lower limb superficial Furstein DNAP 737 2024 Spinothalamic Tract Divisions Direct route: Neospinothalamic/lateral Spinal cord thalamus A-delta fibers Indirect route: Paleospinothalamic/ventral Spinal cord reticular formation thalamus C fibers Furstein DNAP 737 2024 Spinothalamic Tract Divisions Neospinothalamic tract Paleospinothalamic tract Direct route Indirect route Fast pain, rapidly conducting Slow pain, dull aching pain, Mechanical & acute thermal pain thermoreception Immediate warning of the Slow, aching reminder that tissue presence, location, and intensity of damage has occurred an injury Innervation: C fibers that have Innervation: A-delta fibers that terminated in lamina I, II, V have terminated in lamina I Furstein DNAP 737 2024 Dorsal Column Pathway Also referred to as the dorsal column-medial lemniscus As axons enter this pathway, they take on a positional arrangement Axons from the lower levels lie medially Axons from the upper levels lie laterally Separated into two tracts: 1. Fasciculus gracilis (axons from lower body/legs) 2. Fasciculus cuneatus (axons from upper body/arms) Furstein DNAP 737 2024 Dorsal Column Pathway First-order axons in the dorsal column rapidly travel ipsilaterally and terminate in the medulla where they synapse with second- order neurons Axons in this pathway mediate sensation & proprioception Axons decussate the midline of medulla and ascend the brainstem as a bundle called the medial lemniscus Second-order neurons terminate in the thalamus and synapse with a third-order neuron Furstein DNAP 737 2024 Trigeminal Pathway Carries sensory information from the face, head, mouth, and nasal cavity Axons enter the brain stem at the level of the pons or the mesencephalic nuclei in the midbrain Axons carry information similar to that of the dorsal column pathway (touch/pressure/vibration/proprioception) Furstein DNAP 737 2024 Alternative Pain Pathways Spinoreticular tract Mediates arousal & autonomic responses to pain Spinomesencephalic tract May active antinociceptive pathways Spinohypothalmic & spinotelencephalic tracts Evoke emotional behavior Spinocervical tract Alternative pathway for pain Fibers in the dorsal columns Responsible for light touch & proprioception Furstein DNAP 737 2024 Second-Order Neuron Cell body location varies based on ascending pathway Location that the axon decussates is dependent upon the ascending pathway the particular neuron is located in Dorsal column-medial lemniscal pathway: axons stretch from the medulla to the thalamus Spinothalamic pathways: axons stretch from the dorsal horn in the spinal cord to the thalamus Two types of second-order neurons: 1. Wide dynamic range 2. Nociceptive-specific Furstein DNAP 737 2024 Types of Second-Order Neurons Wide dynamic range (WDR) Receive both noxious and non-noxious input Most prevalent cell type in the dorsal horn Large receptive fields Present in lamina III-V Most abundant in lamina V Receive input from A-beta, A-delta, & C fibers Increase their firing rate exponentially (“wind-up”) Furstein DNAP 737 2024 Types of Second-Order Neurons Nociceptive-specific Serve only noxious stimuli Have small receptive fields Normally silent; only respond to high-threshold noxious stimulation Present in lamina I (primarily), II, V, X Receive input from A-delta & C fibers Furstein DNAP 737 2024 Ascending Pathways Furstein DNAP 737 2024 Neurotransmitters Furstein DNAP 737 2024 Neurotransmitters Pain Initiators Pain Inhibitors Glutamate GABA Serotonin Substance P Endorphins Calcitonin gene-related peptide Enkephalins Asparate Dynorphin Bradykinin Glycine Adenosine Prostaglandins Norepinephrine Acetylcholine ATP Furstein DNAP 737 2024 Key Excitatory Neurotransmitters Associated Neurotransmitter Class Released by Effect on receptor on nociception postsynaptic membrane Glutamate Amino acid A-delta fibers Excitatory AMPA, NMDA Substance P Neuropeptide C fibers Excitatory NK-1 Furstein DNAP 737 2024 Quick Review: Second-Order Neurons Two primary ascending pathways for sensory information: 1. ____________________________________ 2. ____________________________________ The ____________ is primarily responsible for touch, pressure, vibration, and proprioception The _______________ is primarily responsible for pain and temperature sensations Furstein DNAP 737 2024 Quick Review: Second-Order Neurons The dorsal column pathway has two tracts: 1. __________________ 2. __________________ and decussates at the level of the ________. The spinothalamic tract has two tracts: 1. ___________________ 2. ___________________ and decussates at the level of the _________. Furstein DNAP 737 2024 Test Your Knowledge In the substantia gelatinosa, _____________ is released following the synapse of C fibers with interneurons, which acts to __________ the concentration of substance P. 1. Endorphins/increase 2. Glutamate/reduce 3. GABA/increase 4. Enkephalin/reduce Furstein DNAP 737 2024 Test Your Knowledge Which section of the spinal cord is responsible for carrying fast pain and temperature? Which direction does this pathway move? 1. Lateral spinothalamic tract/ascending 2. Medial spinothalamic tract/ascending 3. Dorsal column system/ascending 4. Dorsal column system/descending Furstein DNAP 737 2024 Think BIG, start small… Information Painful sent to the Reaction stimulus brain Furstein DNAP 737 2024 Third-Order Neurons Cell body located in the thalamic relay nuclei Axons synapse in the thalamus with second order neurons (specifically in the ventro-posterior thalamus) Axons terminate on the somatosensory cortex Area I located in the postcentral gyrus of the parietal cortex Area II located in the superior wall of the Sylvian fissure Furstein DNAP 737 2024 Third-Order Neurons Send fibers to areas of the postcentral gyrus of the parietal cortex & superior wall of the Sylvian fissure Furstein DNAP 737 2024 Third-Order Neurons Somatosensory cortex Sensory aspects of pain Anterior cingulate cortex Emotional distress associated with pain Limbic cortex Insular cortex Linked to emotion, associated with addiction Furstein DNAP 737 2024 Descending Pain Pathway Responsible for pain inhibition Descending neurons originate in the periventricular & periaqueductal gray Transmit through the nucleus raphe magnus to the substantia gelatinosa via descending dorsolateral funiculus Upon reaching Rexed’s lamina II, synapse with interneurons Furstein DNAP 737 2024 Periaqueductal Gray Matter Located around the cerebral aqueduct within the tegmentum of the midbrain Initiates pathway for pain inhibition Releases both enkelphalin & GABA Furstein DNAP 737 2024 Nucleus Raphe Magnus Thin midline nucleus located in the pons & upper medulla Transmit second-order signals via the dorsolateral columns in the spinal cord to the dorsal horns of the spinal cord 5-HT (serotonin) released from the raphe nuclei descends to the dorsal horn of the spinal cord where it forms excitatory connections with the inhibitory interneurons located in lamina II When activated, these interneurons release either enkephalin or dynorphin which binds to mu-opioid receptors Furstein DNAP 737 2024 Descending Pain Pathway In the SG, interneurons release enkephalins that inhibit further release of substance P, resulting in spinal analgesia In addition, the action potentials descending in the dorsolateral funiculus hyperpolarize cell bodies of the second-order neurons, thereby limiting the number of action potentials ascending the spinothalamic tract Furstein DNAP 737 2024 Key Inhibitory Neurotransmitters Neurotransmitter Released by Effect on nociception Enkephalin Periaqueductal Gray Matter Inhibitory Serotonin Nucleus Raphe Magnus Inhibitory Furstein DNAP 737 2024 Quick Review: Third-Order Neurons Third-order neurons transmit information from the thalamus to the somatosensory cortex Inhibitory neurons originate in the periventricular & periaqueductal gray Inhibitory signals travel via the descending pathway (passing through the nucleus raphe magnus) to the spinal cord Furstein DNAP 737 2024 Quick Review: Third-Order Neurons The primary neurotransmitters responsible for the inhibition of pain are: 1. __________ 2. __________ 3. __________ Enkephalin-releasing interneurons in Rexed’s lamina II inhibit the further release of __________ Furstein DNAP 737 2024 Furstein DNAP 737 2024 Question What is the role of the periventricular & periaqueductal gray in the pain pathway? Furstein DNAP 737 2024 Anatomy of Pain Furstein DNAP 737 2024 Transduction Pain initiation phase Stimuli sensed by mechanoreceptors, thermoreceptors, and nociceptors Furstein DNAP 737 2024 Transmission Action potentials are transmitted along afferent axons to the dorsal horn of the spinal cord Ascending pathways relay sensory input to the thalamus and somatosensory cortex Furstein DNAP 737 2024 Modulation Augmentation or suppression of pain Many areas of the brain involved Somatosensory cortex Hypothalamus Pons Periaqueductal gray Periventricular gray The release of inhibitory neurotransmitters leads to the inhibition of noxious input in the dorsal horn of the spinal cord Furstein DNAP 737 2024 Perception Decoding and interpretation of afferent input that occurs in higher cortical structures Conscious, sensory experience Furstein DNAP 737 2024 Putting it all together… Furstein DNAP 737 2024 Putting it all together… Furstein DNAP 737 2024 Theories of Pain Furstein DNAP 737 2024 Descartes’ Theory of the Pain System Described pain as a perception that exists in the brain and makes the distinction between the neural phenomenon of sensory transduction and the perceptual experience of pain Furstein DNAP 737 2024 Specificity Theory of Pain Bell & Shaw (1868) offered an alternative perspective about the organization of the the nervous system Fundamental tenet is that each modality has a specific receptor and associated sensory fiber (primary afferent) that is sensitive to one specific stimulus The pathways for pain transmission are as specific as those for other senses, such as smell Furstein DNAP 737 2024 Specificity Theory of Pain Proposes that free nerve endings in the skin act as pain receptors, accept sensory input, and transmit this input along highly specific nerve fibers. These fibers then synapse in the dorsal horn, cross-over to the anterior and lateral spinothalamic tracts, and ascend to the thalamus Fails to account for differences in pain perception among individuals and does not take into account physiologic variables Furstein DNAP 737 2024 Intensity Theory of Pain First conceptualized by Plato, later reiterated by Darwin Defined pain, not as a unique sensory experience but rather, as an emotion that occurs when a stimulus is stronger than usual Competed with the Specificity Theory of Pain and ultimately lost support when proponents of the Specificity Theory postulated the existence of nociceptors Furstein DNAP 737 2024 Intensity Theory of Pain Pain is perceived only if the stimulus is sufficient in intensity and/or frequency Stimulation of any sensory receptor will cause pain if the stimulus is excessive If the intensity of the stimulation is below the threshold for tactile perception, summation must occur for the sub-threshold stimuli to become unbearably painful Furstein DNAP 737 2024 Pattern Theory of Pain 1929, J.P. Nafe postulated a “quantitative theory of feeling” Ignored the findings of specialized nerve endings much of the work supporting either the Specificity Theory or Intensity Theory of Pain Sensory impulses are coded according to the number of receptors stimulated and the rate of their discharge Furstein DNAP 737 2024 Gate Control Theory of Pain Melzack & Wall (1965) accepted that there are nociceptors and touch fibers Proposed that these fibers synapse in two different regions within the dorsal horn Proposed that signals produced in primary afferents from stimulation of the skin were transmitted to one of three regions in the spinal cord: 1. The substantia gelatinosa 2. The dorsal column 3. Cells called “transmission cells” Furstein DNAP 737 2024 Gate Control Theory of Pain Proposed that the “gate” in the spinal cord is the substantia gelatinosa in the dorsal horn Therefore, the substantia gelatinosa modulates the transmission of sensory information from the primary afferent neurons to transmission cells in the spinal cord Furstein DNAP 737 2024 Gate Control Theory of Pain The gating mechanism is controlled by the activity of the large and small fibers Small fibers (pain sensations) facilitate/open the gate Large fibers (non-pain sensations) inhibit/close the gate Furstein DNAP 737 2024 Four Most Influential Pain Theories Moayedi, M., & Davis, K. D. (2013). Theories of pain: from specificity to gate control. Journal of neurophysiology, 109(1), 5-12. Furstein DNAP 737 2024 Pain Theory Shortcomings None of the discussed shortcomings adequately account for the complexity of the pain system Focus is placed on cutaneous pain and fails to account for pain relating to deep tissue, visceral, or muscular pain Gate Control Theory was fraught with oversimplifications and based on flawed concepts relating to neural architecture Furstein DNAP 737 2024 Multidimensional Aspects of Pain 1968, Melzack & Casey described pain as being multidimensional and complex, with sensory-discriminative, affective-motivational, and cognitive-evaluative components More recently, pain has been shown to affect and interact with motor systems Most recently (2011), experimental data highlights the differences between the peripheral encoding of nociceptive stimuli and CNS processing and perception of pain Furstein DNAP 737 2024 Questions? Thank you!