3.4 Pain PDF

3.4 Pain Dr. Veronica Campanucci Objectives for Section 3.4: To understand mechanisms involved in the transduction of sensory signals. To understand sensory processes involved in pain. Readings from Kandel: The Somatosensory System Chapter 18 Pain...

3.4 Pain Dr. Veronica Campanucci Objectives for Section 3.4: To understand mechanisms involved in the transduction of sensory signals. To understand sensory processes involved in pain. Readings from Kandel: The Somatosensory System Chapter 18 Pain Chapter 20 What is pain? The ability to detect noxious stimuli is essential to an organism’s survival and wellbeing Acute vs chronic Changes in pain perception: Reduced sensitivity (can involves other issues) Increased sensitivity (Allodynia and hyperalgesia) Nociception is the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors (Basbaum and Jessell, 2000). Noxious stimuli activate thermal, mechanical, and polymodal nociceptors Many organs in the periphery (skin, and subcutaneous structures such as joints and muscles) have specialized sensory receptors that are activated by noxious insults (nociceptors). What is a nociceptors? They are simply the free nerve endings of primary sensory neurons Tree types: 1) Thermal nociceptors: activated by temp. > 45°C or < than 5°C. They include myelinated Aδ fibers (5-30 m/s) and unmyelinated C-fibers (1 m/s). 2) Mechanical nociceptors: activated by intense pressure applied to the skin. Also endings of myelinated Aδ axons. 3) Polymodal nociceptors: activated by high-intensity mechanical, chemical, or thermal (both hot and cold) stimuli. Predominantly of unmyelinated C fibers. These three classes of nociceptors are widely distributed in skin and deep tissues and are often co-activated. Nociceptive transmission (Aδ and C fibers) No pain: A fibers: proprioception. A fibers: touch. Pain: A fibers: pain and temp. C fibers: pain, temp and itch. When a hammer hits your thumb, you initially feel a sharp pain (“first pain”) followed by a more prolonged aching and sometimes burning pain (“second pain”). First pain (sharp): transmitted by Aδ fibers that carry information from damaged thermal and mechanical nociceptors. Aδ fibers conduct impulses at a speed of about 10–20 m/s, which is fast enough to cause a rapid withdrawal of the affected body part Second pain (slow dull): transmitted by C fibers that convey signals from polymodal nociceptors. The TRP channel superfamily (thermal receptors) Figure 20-2 Are cation non-selective channels, composed of 4 subunits (tetramers), each containing 6 transmembrane domains. The pore region is between S5 and S6. Some (TRPV1 and TRPM8) have a voltage-sensor. Different sensitivity to heat or cold. Nociceptors signals are sent to the dorsal horn Lamina I: A and C fibers (nociceptive). Lamina II (substantia gelatinosa): excitatory and inhibitory interneurons. Laminae III and IV: mixture of local interneurons and supraspinal projection neurons. Many of these neurons receive input from Aβ afferent fibers that respond to innocuous cutaneous stimuli, such as deflection of hairs and light pressure. Lamina V: wide variety of noxious information and project to the brain stem and thalamus. They receive information from both somatic and visceral nociceptors. Lamina VI: receives large diameter primary afferent fibers that innervate muscles and joints. These neurons are activated by innocuous joint movement and do not contribute to nociception. Laminae VII and VIII: information less organized, usually from large body areas (diffuse pain) Ascending nociceptive pathways 1) Spinothalamic tract (brown): is the most prominent ascending nociceptive pathway (laminae I and V through VII), and it terminates in thalamic nuclei. 2) Spinoreticular tract: axons of projection neurons in laminae VII and VIII. This tract terminates in both the reticular formation and the thalamus. This pathway is implicated in diffuse, poorly localized pains. 3) Spinoparabrachial tract (red): axons of projection neurons in laminae I and V, project to the parabrachial nucleus at the level of the pons. Parabrachial neurons project to the amygdala, a critical nucleus of the limbic system, which regulates emotional states. 4) Spinohypothalamic tract: axons of neurons found in spinal cord laminae I, V, VII, and VIII. These axons project to hypothalamic nuclei that serve as autonomic control centers involved in the regulation of the neuroendocrine and cardiovascular responses that accompany pain syndromes. The gate control theory of pain (1960) Pain is a perception that can be influenced by a mechanism in the spinal cord. The theory states that the spinal cord has a "gating" mechanism that controls whether pain signals are sent to the brain. The "gate" can be open or closed, and the level of pain experienced depends on the state of the gate. The projection neuron is excited by both (A and C fibres) classes of sensory neurons and inhibited by interneurons in the superficial dorsal horn. The two classes of sensory fibers also terminate on the inhibitory interneurons: - the C fibers inhibit the interneurons “opening the gate” - the Aβ fiber excite the interneurons “closing the gate” Possible explanation for why shaking or rubbing the hand following injury is a reflexive behavior and may alleviate pain by activating large diameter (A) fibers, which suppress pain transmission to the brain. Referred pain Is a condition in which pain from injury to a visceral tissue is perceived as originating from a region of the body surface. The convergence of somatic and visceral nociceptive inputs onto lamina V neurons provides one explanation for referred pain. E.g., Patients with myocardial infarction frequently report pain from the left arm and chest. Reasons: - A single lamina V neuron receives sensory input from both skin and viscera (heart), and thus a signal from this neuron does not inform the brain about the source of the input. - The axons of nociceptive sensory neurons branch in the periphery, innervating both skin and visceral targets Alterations in nociception Two common changes in pain perception: 1) Allodynia: pain in response to stimuli that are normally innocuous (állos = other). For example, a light stroking of sunburned skin, the movement of joints in patients with rheumatoid arthritis, and even the act of getting out of bed in the morning after a vigorous workout. Nevertheless, patients with allodynia do not feel pain constantly; in the absence of a peripheral stimulus, there is no pain. 2) Hyperalgesia: an exaggerated response to noxious stimuli (typically report persistent pain in the absence of sensory stimulation). Persistent (or chronic) pain: 1) Nociceptive pain: results from the activation of nociceptors in the skin or soft tissue in response to tissue injury, and it usually occurs with inflammation. Nociceptive pain is treated with nonsteroidal anti-inflammatory (NSAIDS) drugs or, when severe, with opiates such as morphine. 2) Neuropathic pain: results from direct injury to nerves in the peripheral or central nervous system. Often accompanied by a burning or electric sensation. Examples: regional pain syndrome, post-herpetic neuralgia (shingles), trigeminal neuralgia, phantom limb pain (after limb amputation), etc. Neuropathic pains do not respond to NSAIDS drugs and are generally poorly responsive to opiates. The first nociceptive synapse Glutamate is the primary neurotransmitter released by primary sensory neurons. Neuropeptides are released as co-transmitters by many nociceptors. These peptides include substance P, calcitonin gene–related peptide (CGRP), somatostatin, and galanin. Glutamate is stored in small vesicles and peptides are sequestered in large, dense-core vesicles. e.g., substance P is released from the central terminals of nociceptive afferents in response to tissue injury or after intense stimulation of peripheral nerves. Although the physiological actions of glutamate and neuropeptides on dorsal horn neurons are different, these transmitters act coordinately to regulate the firing properties of dorsal horn neurons. Propagation of pain signals Zemel et al. 2018. https://doi.org/10.3389/fnmol.2018.00253 Peripheral ending: Central ending: Substance P & CGRP Glutamate & Neuropeptides Peripheral sensitization The sensitization of peripheral nociceptors Damaged tissues release a cocktail containing peptides and proteins (bradykinin, substance P, nerve growth factor, ATP, histamine, 5HT, prostaglandins, leukotrienes, and acetylcholine). The cocktail decreases the threshold of nociceptor activation Bradykinin (active pain-producing agent), activates Aδ and C nociceptors. Neurogenic inflammation: bradykinin and prostaglandins from insured tissues activate or sensitize nociceptors. Nociceptors release of substance P and CGRP. Substance P acts on mast cells, which release histamine. Histamine directly excites nociceptors. Substance P also produces plasma extravasation and edema, and CGRP produces dilation of peripheral blood vessels (red skin); the resultant inflammation causes additional liberation of bradykinin (further spreading). Increased sensitivity of nociceptors by modulating TRP channels Bradykinin (BK), which is released form tissues after injury, binds to G protein–coupled receptors on the surface of primary afferent neurons to activate phospholipase C (PLC), leading to the hydrolysis of membrane phosphatidylinositol bisphosphate (PIP 2), the production of inositol 1,4,5- trisphosphate (IP 3), and the release of Ca2+ from intracellular stores. Activation of protein kinase C (PKC) regulates TRP channel activity by phosphorylation. The TRPV1 channel is sensitized, leading to channel opening and Ca2+ influx. Central sensitization - pathology Enhancement of excitability in dorsal horn neurons (involves NMDA receptors) Repeated exposure to noxious stimuli results in long-term changes in the dorsal horn neurons. These prolonged changes in the excitability of dorsal horn neurons constitute a “memory” of the state of C-fiber input. Central sensitization of pain circuitry in the dorsal horn is the process that can decrease pain thresholds (allodynia) and lead to spontaneous pain (ie, ongoing pain in the absence of peripheral stimulation). Central sensitization is a major contributor to neuropathic pain due to nerve injury. Analgesia Analgesia is the insensibility to pain without loss of consciousness. Opioid receptors: mu (μ), delta (δ), kappa (κ), and orphanin FQ. Endogenous opioids: enkephalins, β- endorphins, and dynorphins. Morphine controls pain by activating opioid receptors and by mimicking the actions of endogenous opioid peptides The dorsal horn contains interneurons that express enkephalin and dynorphin, and the terminals of these neurons lie close to synapses formed by nociceptive sensory neurons and dorsal horn neurons. μ, δ, and κ receptors are located on the terminals of the nociceptive sensory neurons and on the dendrites of dorsal horn neurons. C-fiber nociceptors have more μ receptors than the Aδ nociceptors. Opioids on nociceptor signal transmission - Presynaptic (DRG): reducing Ca+ entry and neurotransmitter release. - Postsynaptic (projection neuron): Increase K+ conductance, hyperpolarization and increasing activation threshold (hyposensitivity). Figure 20–19 Self-testing questions Which are the nerve fibers and membrane receptors involved in pain transmission? (include first and second pain) What are the components of the pain pathways from the DRG nociceptors to the somatosensory cortex? Using the gate theory of pain, explain why rubbing and shaking have an analgesic effect after pain stimulation of the skin. Explain hyperalgesia and allodynia. Explain peripheral vs. central sensitization. Why is morphine used an analgesic?