L12. Physiology of Pain PDF

12 Physiology of Pain ILOs By the end of this lecture, students will be able to 1. Identify types of pain and how it is perceived via pain receptors 2. Distinguish pathways for pain sensations 3. Describe the peripheral and central mechanisms of hyperalgesia 4....

12 Physiology of Pain ILOs By the end of this lecture, students will be able to 1. Identify types of pain and how it is perceived via pain receptors 2. Distinguish pathways for pain sensations 3. Describe the peripheral and central mechanisms of hyperalgesia 4. Discuss referred pain and its mechanism 5. Explain peripheral and central sensitization 6. Define neuropathic pain and its main causes Pain is defined as unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is termed nociceptive and nociceptive means sensitive to noxious stimuli. Pain Receptors Nociceptors are sensory receptors that detect signals from damaged tissue. Nociceptive afferents do not have specialized receptors; they use free nerve endings and most are polymodal, i.e. they respond to more than one kind of stimulus, such as chemical, thermal or mechanical stimuli. Nociceptors are free (bare) nerve endings. They transduce a variety of noxious stimuli into receptor potentials, which in turn initiate action potential in the pain nerve fibers. Free nerve endings are found in all parts of the body except the interior of the bones and the brain itself. Pain receptors are divided into four categories based on function: 1. High threshold mechano-nociceptors or specific nociceptors: (mechanical stimulation such as pinching, cutting or stretching). 2. Thermal nociceptors, (thermal stimuli). 3. Chemical nociceptors, (chemical substances). 4. Polymodal nociceptors, which respond to high intensity stimuli such as mechanical, thermal and to chemical substances like the previous three types. Factors that Activate Nociceptors Nociceptors respond to a stimulus causes tissue damage. The damage of tissue results in a release of a variety of substances from lysed cells as well as from new substances synthesized at the site of the injury. These substances include: - Globulin and protein kinases: which are believed to be one of the most active pain- producing substances. - Arachidonic acid. Arachidonic acid is one of the chemicals released during tissue damage. It is then metabolized into prostaglandin (and cytokines). - Histamine. Tissue damage stimulates the mast cells to release histamine to the surrounding area. - Nerve growth factor (NGF). 1  - Substance P (SP) and calcitonin gene-related peptide (CGRP) are released by injury. - Potassium - K+. Most tissue damage results in an increase in extracellular K+. - Serotonin (5-HT), acetylcholine (ACh), low pH (acidic) solution, and ATP. - Muscle spasm and lactic acid. When muscles are hyperactive or when blood flow to a muscle is blocked, lactic acid concentration increases, and pain is induced. Pain Fibers, there are two types of pain fibers, A delta fiber (group III fibers) C fibers (group IV fibers) - 2-5 mm in diameter, - 0.4-1.2 mm in diameter - myelinated, - unmyelinated - have a fast conduction velocity (5- - have a slow conduction velocity (0.5-2.0 40 meters/sec), meters/sec) - and carry information mainly from - activated by a variety of high-intensity the nociceptive-mechanical or mechanical, chemical and thermal mechano-thermal nociceptors. stimulation and carry information from - Their receptive fields are small. polymodal nociceptors Therefore, they provide precise - Their receptive fields are large, therefore, localization of pain. less precise for pain localization. Fig. 1: Pain fibers Types of pain Nociceptive (acute) pain is elicited by a brief noxious stimulus such as pinprick and induces a flexion withdrawal response to the stimulus. This type of pain is an adaptive sensation whose primary function is to protect the body from injury; it is an early warning alarm system. Acute pain is characterized by activation of nociceptors for a limited duration and is mediated mainly by A delta fibers. Nociceptive pain may result from activation of either superficial or deep nociceptors. 2 Muscle or visceral Pain Results from stimulation of nociceptors in the muscles or viscera. Visceral and muscle pain is poorly localized, due to the lower innervation densities of these tissues, and is periodic. visceral afferents are insensitive to direct trauma but very sensitive to distension (of hollow-walled muscular organs), ischemia or inflammation. Prolonged pain (e.g. sunburn) injury to the body has already occurred and the biological function of pain is to prevent further damage, assist healing and tissue repair. It does this by the development of areas of hypersensitivity in and around the injury site, which are the result of a decreased activation threshold of nociceptors–a phenomenon called peripheral sensitization. The pain recedes once healing has occurred. Chronic (neuropathic) pain is pain that has been present for at least 2–3 months. Chronic pain is defined as; pain resulting from disease or damage to the peripheral or central nervous systems, and from dysfunction of the nervous system. Thus, it covers a wide range of conditions such as muscle and joint pain disorders such as fibromyalgia and back pain where there is no clear nerve damage and to pain in diseases such as diabetes, cancer and AIDS. The quality of pain sensations is distinct from that seen in acute pain. In neuropathic pain, the pain persists in the absence of the initial injury. Chronic pain often results from abnormal sensitivity of nociceptors and pathological changes in the nervous system. Features of neuropathic pain - Abnormal pain quality—burning, stabbing. - Pain is poorly localized and diffuse - Pain intensity altered by emotion and fatigue - Onset of pain is immediate or delayed after injury - Sympathetic nervous system dysfunction may be present, vasomotor (regulation of blood vessels) and sudomotor (stimulation of sweat glands) changes Sensitization of peripheral receptors Tissue damage and inflammation result in the release of inflammatory molecules which lower the activation threshold of nociceptors (sensitize peripheral nociceptors).When the response to a normally painful stimulus is heightened (more pain felt than usual), it is referred to as hyperalgesia, which include the expression of more Na+ channels. Overexpression of Na+ channels in clusters on the peripheral branches of the A and C fibers can lead to spontaneous discharges and lower the threshold for signaling. Hyperalgesia can be differentiated into primary and secondary. Primary hyperalgesia occurs in the region of damaged skin and is a result of receptor sensitization. Secondary hyperalgesia occurs in the skin immediately bordering the damaged tissues. Although receptor sensitization may contribute to secondary hyperalgesia, there is likely to be a central component as well. Central sensitization: changes in the synapses of the posterior horn of the spinal cord. Changes in glutamate receptor with insertion of more glutamate receptors in the postsynaptic second- 3 order neuron lead to increased excitability of this neuron and facilitated synaptic transmission. Collectively, this leads to increases in spontaneous activity (paresthesias, dysesthesias) and a reduced threshold for pain perception (hyperalgesia). In addition, some nociceptor neurons can be converted to wide dynamic range neurons that now receive input from all types of sensory fibers which typically occurs following nerve injury. This will result in nonnoxious stimuli being interpreted as pain light touch on sunburn (allodynia). Fig. 2: Hyperalgesia- Sensitization Pain pathways (Anterolateral system) Different ascending pathways are concerned with pain transmission: the spinothalamic tract (STT), spinoreticular tract (SRT), spinomesencephalic, and spinobulbar tracts Cutaneous nociceptor afferents enter the spinal cord travel up or down 1–2 segments in the Lissauer tract, and then synapse in the posterior horn. Axons of secondary neurons cross the midline in the anterior white commissure and ascend as the anterolateral tract in the spinal cord. The fibers in the anterolateral system are arranged somatotopically, with fibers carrying information from the lower limb located more laterally and those carrying information from the upper limb more medially. The neospinothalamic tract (lateral sensory-discriminative pathway) of the anterolateral system terminates in the ventral posterolateral (VPL) nucleus of the thalamus (fibers from the trigeminal system project to the ventral posteromedial [VPM] nucleus of the thalamus. From the thalamus, fibers project to the primary somatosensory cortex. It is considered as pathway for fast pain and signaling the exact location and severity of the injury and the duration of the pain. Slow pain (second pain) is mediated by C-fibres and signals the emotional aspects of pain. It innervates the non-specific intralaminar nuclei of the thalamus, and the autonomic centres of the reticular formation in the brainstem. The projections to the reticular formation underlie the arousal effects of painful stimuli via activation of the ascending reticular activating system that projects to all areas of the brain. Activation of the reticular formation stimulates noradrenergic neurones in the locus coeruleus, and thus decreases the pain transmission by activating the 4 descending pain modulating systems. Most of their axons cross and ascend in the spinal cord primarily in the anterior region and thus called the anterior spinal thalamic tract. extensive connections between these tracts and the limbic areas such as the cingulate gyrus and the insular cortex, involved in processing the emotional components of pain. Presumed functional roles of cortical areas in pain perception Primairy sensory area I : Pain localization Insular cortex: Regulation of pain-related autonomic activity; pain intensity Anterior cingulate gyrus: attention, affect, anticipatory appraisal of pain; pain modulation Prefrontal cortex: affect, emotion, memory, anticipatory appraisal of pain; pain modulation Referred pain is a pain of visceral origin that is referred to sites of the body that is away from its source and follows the dermatome rule. These sites are innervated by nerves that arise from the same segment of the spinal cord. Examples of referred pain 1. Anginal pain is referred mainly to the retrosternal region, the left shoulder and inner side of the left arm. 2. Gall bladder pain is referred to the tip of the right shoulder and right scapula. 3. In the early stages of inflamed appendix, pain is produced around the umbilicus, later when the parietal peritoneum is irritated, pain becomes localized to the right iliac fossa. Suggested mechanisms of referred pain: afferent convergence onto spinal cord cells that have a cutaneous receptive field. The area of referral is related to the segmental dermatome and is often to skin or muscle. 5 Pain Pathways 6