Pathophysiology of Pain BMS 150 PDF

Pathophysiology of Pain BMS 150 Week 9 References Principles of Neural Science (Eric Kandel) Chapter 20 Principles of Neurology (Adams and Victor) Chapter 7 Neuroscience Online https://nba.uth.tmc.edu/neuroscience/m/s2/chapter06. html Pain - Introduction Definition: unpleasant sensation and emotiona...

Pathophysiology of Pain BMS 150 Week 9 References Principles of Neural Science (Eric Kandel) Chapter 20 Principles of Neurology (Adams and Victor) Chapter 7 Neuroscience Online https://nba.uth.tmc.edu/neuroscience/m/s2/chapter06. html Pain - Introduction Definition: unpleasant sensation and emotional experience associated with actual or potential tissue damage, or described in terms of such damage ▪ The emotional aspect of pain makes it unique – no other sensation has the same ability to impact mood and quality of life Pain perception is very subjective ▪ People can suffer serious injuries during battle or athletic events and feel very little pain (until the event is over or danger has lessened) ▪ People can have little to no evidence of tissue damage but still report experiencing significant amounts of pain Types of Pain and Abnormal Sensation Term Definition Dysesthesia Any abnormal sensation described by a patient as unpleasant Paresthesia A sensation that is typically described as “pins-and-needles” or “prickling”, but is not notably unpleasant Analgesia Reduction or loss of pain perception Anaesthesia Reduced perception of all touch & pain sensation Hypoalgesia Decreased sensation and raised threshold to painful stimuli Hyperalgesia Exaggerated pain response from a normally painful stimulus Allodynia Abnormal perception of pain from a normally non-painful mechanical or thermal stimulus Hyperesthesia Exaggerated perception of a touch stimulus Causalgia Burning pain in the distribution of a peripheral nerve Pain is puzzling Spinothalamic tract carries pain sensation The neuroanatomical “localization” of pain is difficult to fully define ▪ Lesions of the thalamus, cortex, and other “higher” locations of the spinothalamic tract often cannot completely eliminate pain Only multiple lesions of the spinal cord seem to be capable of completely removing painful sensations in a particular area of the body ▪ One cannot elicit pain by stimulating the cortex directly – other areas need to be stimulated (i.e. thalamus, hypothalamus) for pain to be perceived Pain does not exhibit adaptation, unlike almost all other perceptions (touch, taste, smell) The central nervous system regulates perception and transmission of pain from lower levels, using multiple different molecules and pathways Pain transmission can actually cause inflammation in peripheral tissues Physiology of nociception Nociceptors are widely distributed through multiple depths in the skin Neurons with lots of receptors that help us feel pain ▪ “Dermal pain” tends to be described as sharp or burning Nociceptors are also widely distributed through many visceral organs ▪ Skeletal/cardiac muscle – dull, pressure-like pain ▪ Joints (synovium) and bones (periosteum) – many different characteristics (sharp, dull, aching) ▪ Blood vessels – usually dull ▪ Nerve roots and meninges ▪ Hollow viscera – often dull, cramping but can be sharp ▪ Mesothelial linings (peritoneum, pleura, pericardium) – often sharp ▪ Many organs can cause a dull pain due to stretching of the capsule Physiology of nociception Types of nociceptors: Thermal nociceptors – activated by temperatures > 45 C or less than 5 C Mechanical nociceptors – activated by intense pressure applied to a structure (i.e. skin) Polymodal nociceptors – activated by high intensity mechanical, chemical, or thermal stimuli Silent nociceptors – receptors that are widely distributed through viscera (but can also be found in the skin) that do not normally transmit pain information ▪ Only “awakened” in a setting of continuous damage or inflammation Physiology of nociception All nociceptors appear to be very simple neurons under the microscope – two major types: C fibres – unmyelinated axons with cell body in the dorsal root ganglia ▪ Conduction velocity: 0.5 – 2 m/sec Slow ▪ Responsible for conducting slow pain and thermoception (temperature) ▪ Often dull, poorly-localized pain (large receptive fields) ▪ C-fibres also carry itching sensations Physiology of nociception All nociceptors appear to be very simple neurons under the microscope – two major types: A-delta fibres – myelinated axons with cell body in the dorsal root ganglia ▪ Conduction velocity: 12 – 30 m/sec ▪ Responsible for conducting sharp, “pricking” pain as well as some thermoception (temperature) ▪ Usually well-localized (smaller receptive fields) What can nociceptors detect? Very wide range of ion channels expressed in the free nerve endings, which allows them to detect a wide range of stimuli that can be associated with damage to tissue The transient-receptor potential receptors (TRP) are capable of recognizing a wide range of tissue insults: ▪ Cold and heat ▪ Low pH and free radicals ▪ Capsaicin ASIC receptors are receptors that can detect low pH (typical of ischemia or tissue damage) Acid-sensing ion channels? Stomach should not have a lot of these receptors Having them ie near the esophagus can help if they sense stomach acid rising up where it shouldn’t be What can nociceptors detect? Nociceptors also express receptors for molecules that are released during inflammatory processes ▪ Prostaglandins – most are G-protein-coupled receptors that block potassium channels (leading to depolarization) ▪ Bradykinin – activated by pro-inflammatory, procoagulant processes protein that circulates in the bloodstream (kininogen) is activated to form bradykinin in situations involving tissue damage ▪ Histamine ▪ Substance P – released from a wide range of tissues ▪ Serotonin, acetylcholine, ATP Relates to emotional aspect of pain What can nociceptors detect? Activation of some receptors in found in nociceptive neurons can increase the activation of other receptors ▪ Example – bradykinin can increase the activation of TRP receptors Bradykinin sensitizes the TRP receptor, making it more likely to open Neuroanatomical Pain Pathways Spinothalamic tract is the major nociceptive sensory pathway peripheral afferent pain fibers of both A-δ and C types have their cell bodies in the dorsal root ganglia ▪ central extensions of these nerve cells project, via the dorsal root, to the dorsal horn of the spinal cord ▪ Within the spinal cord, many of the thinnest fibers (C fibers) form a discrete bundle, the tract of Lissauer Peripheral afferent fibres usually terminate within the same segment as their spinal nerve ▪ Some extend rostrally a segment or two ▪ FYI – synapse in a wide range of dorsal horn lamina I, II, V, VII ,VIII Neuroanatomical Pain Pathways 2nd neuron crosses over to other side before ascending to the brain Somatosensory area Spinothalamic tract – basic review Ie feeling pain on right side, 2nd order neuron crosses over to left side A delta as well as C fibres Spinothalamic Tract – additional details Pain related to the face will be carried by trigeminal nerve Ascending pain pathways – additional details The fibres of the spinothalamic tract usually cross over (2nd order neurons) two or three levels superior to where the 1st-order neurons enter the spinal cord ▪ The i fibres of 1st order neurons tend to ascend in a small fibre seem bundle (the tract of Lissauer) before crossing over and synapsing Another tract – the paleospinothalamic pathway – travels a somewhat different route ▪ Fibres ascend in the cord more↳ medially ▪ Project through the medulla and synapse within a different set of thalamic nuclei = (the intralaminar nuclei) ▪ Also synapse in a wide variety of other brainstem areas: Midbrain reticular formation, peri-aqueductal gray matter, hypothalamus * May be responsible for much of the emotional distress and mood impacts of pain E ↳ Ascending pain pathways – additional details Visceral pain sensation likely ascends along the anterior spinothalamic tract, and better-localized skin-associated pain sensation likely ascends via the lateral spinothalamic tract These areas are very close together —> neurons can get confused where the signals are coming from —> referred pain The concept of fast pain and slow pain Fast pain – welllocalized, sharp pain carried by A-delta fibres Slow pain – poorerlocalized, duller ▪ Carried by Cfibres ▪ Tends to last longer Top-Down Modulation of Pain Transmission We have a built-in analgesia system ▪ Stimulation of certain brainstem areas can cause profound analgesia – the most famous of these brainstem areas is the periaqueductal gray matter ▪ Descending tract that directly inhibits pain conduction at the level of the spinal cord (levels I, II, V in the dorsal horn) ▪ Present in animals and in humans – mediated by opiate receptors ▪ The small “cones” indicate sites where opioid agonists or antagonists work on this system Top-Down Modulation of Pain Transmission We have a built-in analgesia system ▪ Norepinephrine and serotonergic systems from the brainstem project to the spinal cord and activate inhibitory interneurons ▪ They accomplish this by releasing enkephalins that Less NT release both inhibit nociceptor & less receptors presynaptic NT release (substance P, glutamate) and inhibit projection neurons Top-Down Modulation of Pain Transmission The opioid receptor responsible is likely the mu receptor – it has a wide distribution, but is found in the spinal cord ▪ Endogenous agonists of opioid receptors are called opiates ▪ Opiates include enkephalins, endorphins, and dynorphins ▪ All are small peptides and have a sequence of Tyr-Gly-Gly-Phe C-fibres have higher concentrations of mu opioid receptors ▪ likely why activation of this receptor type brings the most relief Because these fibres carry more chronic pain Gate Theory of Pain Control Presence of nonnociceptive stimuli at a similar site/spinal level tends to reduce pain perception ▪ Why rubbing an area that is sore can reduce the intensity of the pain at that site, to some degree ▪ The non-nociceptive stimulus (i.e. touch) activates an inhibitory interneuron that inhibits the projection interneuron Sensitization and Hyperalgesia When peripheral tissue is damaged, can result in an increase in pain sensitivity or hyperalgesia ▪ This condition can be elicited by sensitizing peripheral nociceptors through repetitive exposure to noxious stimuli Chemicals that are thought to be responsible include: ▪ Bradykinin Sensitized receptors to capsaicin & spice ▪ Histamine ▪ Prostaglandins ▪ ATP, acetylcholine, serotonin – all of these are released from activated platelets or damaged endothelial cells Sensitization and Hyperalgesia Many of these molecules are released during states of tissue damage, and they can act peripherally, at the “dendrite” of the nociceptor ▪ This is known as peripheral sensitization – molecules released at the site of tissue damage or inflammation increase the effectiveness of nociception ▪ Happens very quickly Over time, central sensitization can develop Chronic ▪ Central sensitization occurs with synaptic remodelling in the dorsal horn – leads to increased effectiveness of pain transmission C fibres are more likely to exhibit central sensitization than Adelta fibres Central Sensitization Pro-inflammatory cytokines → release of nerve growth factor from mast cells ▪ NGF increases the release of BDNF from C fibres ▪ This increases the excitability of “pro-pain” dorsal horn networks and C fibre transmission Neurogenic Inflammation Interestingly, action potentials can actually move BOTH ways down a pain fibre (in particular, a C fibre) ▪ From periphery → spinal cord = orthodromic ▪ From spinal cord → periphery = antidromic C fibres can release numerous substances, but in particular substance P and CGRP, from dendrites into peripheral tissues when action potentials move antidromically ▪ Substance P can cause mast cell degranulation, vasodilation, and edema ▪ CGRP can cause vasodilation ▪ These substances can increase inflammation – this is known as neurogenic inflammation (next slide) Neurogenic Inflammation Although this seems like a very maladaptive and unpleasant process, it does help us protect a damaged tissue from further damage ▪ Recruitment of leukocytes ▪ Limitation of use and protection of the injury May exacerbate the pain of inflammatory disorders, though, in conjunction with central sensitization A Little About Substance P No, the “P” doesn’t stand for “Pain” ▪ Stands for powder (how it was isolated) Released by a wide variety of cells in the nervous system and elsewhere Most famous for being released by C fibres, but is also responsible for: ▪ ▪ ▪ ▪ ▪ Augmenting inflammation Learning & neurogenesis Mood disorders Nausea and vomiting Cell growth and angiogenesis Substance P is an 11 a.a. peptide and binds to the NK-1 (neurokinin-1) receptor A Little About Substance P Substance P is likely what makes C fibres transmit impulses for longer periods of time ▪ Remember first pain and second pain? Substance P release → long-lasting depolarization of projection neurons via modulation of other cation channels ▪ A-delta fibres don’t release substance P – therefore their EPSPs from release of glutamate tend to last less time Why Does Nerve Injury Sometimes Cause Pain Instead of Analgesia? Neuropathies frequently cause neuropathic pain – why don’t they just cause analgesia? May be related to the concept of the pain gate ▪ A-beta fibres from “regular sensations” (vibration, touch) tend to stimulate inhibitory interneurons that reduce transmission of pain from projection interneurons ▪ C fibres that carry painful stimuli tend to inhibit the inhibitory interneurons ▪ Therefore, whether we feel pain or not depends on where the balance “sits” between nociceptive and non-nociceptive inputs Injury to nerves tends to reduce the stimuli to the inhibitory interneurons → excessive activation of excitatory interneurons and nociceptive projection neurons Why Does Nerve Injury Sometimes Cause Pain Instead of Analgesia? Pain and Mood Pain perception areas and “mood disorder” areas share similar geographic areas in the CNS ▪ Amygdala, cingulate gyrus, insular cortex ▪ Some of the monoamine areas in the midbrain that release norepinephrine and serotonin are linked to descending modulation of pain as well as the pathophysiology of depression Inflammation can contribute to depression and can also increase the likelihood of central sensitization in the dorsal horn No clear answers have yet been thoroughly proven ▪ However, there is a clear concordance – 65% of patients with depression have one or more chronic pain complaints Referred Pain – A Brief Word Deep pain has indefinite boundaries and its location is distant from the damaged visceral structure ▪ tends to be referred not to the skin overlying the damaged organ but to other areas innervated by the same spinal segment Cutaneous afferents outnumber visceral ones, and visceral afferents often project to multiple spinal levels ▪ One can simplify referred pain as “mixed message” pain where the pain from an organ is confused with well-localized * skin nociception from more defined dermatomes ▪ Example: cardiac structures are “mostly” supplied by T1 – T4 nerves However, C-fibres from the heart can extend all the way to T1 – T2 (inner side of the arm, ulnar side of the hand) [ 31