Nociception Lectures PDF

Nociception Dr Mariana Vargas-Caballero 2 lectures -> General overview of Sensory Systems -> Nociception  Learning Outcomes 1) Define pain and terms associated with nociception. 2) Describe the afferent pathways that mediate pain and temperature. 3) Describe th...

Nociception Dr Mariana Vargas-Caballero 2 lectures -> General overview of Sensory Systems -> Nociception  Learning Outcomes 1) Define pain and terms associated with nociception. 2) Describe the afferent pathways that mediate pain and temperature. 3) Describe the physiological mechanisms needed for the integration of painful stimuli. 4) Describe the descending modulation of these pathways. Most figures and tables from Neuroscience; Purves.  Sensory Internal/ Systems External Process BEHAVIOU ENVIRONME ing R NT Image from northamericanneuropathy.com Two axon branches depart from the soma. One branch runs to the periphery (PNS) and the other to the spinal cord (CNS) The cell bodies (somas) of all somatosensory fibres from the body are located in the dorsal root ganglia (DRG). Signals from face: somas in trigeminal ganglion. First order sensory neurons are pseudounipolar. Two axon branches  First order neurons Dorsal root ganglion (DRG) neurons Mechanosensory. Enters dorsal root and joins dorsal column Pain and temperature fibre makes a connection upon entrance dissociated sensory loss used in clinical diagnos  Nociception/ Temperature Mechanosensatio n (fine-touch, pressure, vibration, proprioception) Proprioception (+ vestibular system)  Classes of somatosensory afferents Sensory Function Receptor Type Axon type Diameter Conduction Velocity Proprioreception Muscle spindle 13 - 20 micrometer 80-120 m/s Touch Merkel, Meissner, 6 - 12 micrometer 35-75 m/s Pacinian, Ruffini cells Pain, Temperature Free nerve endings 1 - 5 micrometer 5-30 m/s Pain, Temp., Itch Free nerve endings 0.2 – 1.5 micrometer 0.5-2m/s Fibre diameter and myelination determine speed of action potential propagation. Sensory Systems: transduction The sensory transduction cascade, where the energy of a stimulus is converted into an electrical signal consists of several key steps: signal transduction current generator potential 1. Weak stimulus 2 Moderate stimulus 3 Strong stimulus (1-3: Generator potential) action potentials 4/5 Spike potential is generated Delmas, et al 2011 Tonic vs. phasic Receptors convey dynamic or static qualities of a stimulus.  Ascending pathways for somatosensation Unconscious Conscious Proprioception Mechanosensation Spinocerebellar tract Pain and temperature: Nociceptive ascending systems (conscious) Body (and posterior Face (and anterior portion portion of the head) of the head) Pain and temperature: Pain and temperature:  Spinothalamic tract  Trigeminothalamic tract a.k.a. anterolateral system (face, oral, through the spinal nucleus of the trigeminal complex). The thalamus (relay station) contains a complete representation of the somatic sensory periphery. Trigeminal Rest of the body  Cortical maps of sensory surfaces Post central gyrus Sensory map exaggerates certain regions according to number/type of peripheral fibres innervating a region.  Cortical integration and signaling. - Thalamic input predominantly layer IV - Cortex sends projections in turn to limbic structures such as the amygdala and hippocampus. - Cortex also sends descending signals (thalamus, brainstem, and spinal cord) Measuring physiological variables: Sugar levels Blood pressure Cardiac function What about pain?  The International Association for the Study of Pain Definition of pain: An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. Sensory Affective (emotional) Affective AutonomicSecondary affect (impact Motor of chronic pain in emotional life) Psychosocial context  Multiple Brain Areas How are Harmful Stimuli Detected? Spinal cord Nociception: The neural process of encoding noxious stimuli. http://www.iasp-pain.org/ Peripheral tissue Terminology  Nociceptive afferents Nociceptors lie near blood vessels between epithelial layers of the skin, the cornea, muscle joints, viscera, the alimentary tract, and in connective tissues. Activated by stimuli that are damaging or potentially damaging. Noxious mechanical, thermal, chemical stimuli. Nociceptor properties can change: inflammation, damage, pathology. Essentially innervate all tissue except brain! https://www.youtube.com/watch?v=_SGfFHbJHwg Image taken from: Pathological pain and the neuroimmune interface Peter M. Grace, Mark R. Hutchinson, Steven F. Maier & Linda R. Watkins Nature Reviews Immunology 14, 217–231 (2014) doi:10.1038/nri3621 David Julius and Ardem Patapoutian  52°C Painful heat >43C causes TRPV1 channels (tetramers) to open in C fibre endings. Ca and Na ions enter and depolarise the cell, causing AP The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept Arpad Szallasi, Daniel N. Cortright, Charles A. Blum & Samer R. Eid Nature Reviews Drug Discovery 6, 357-372 (May 2007) doi:10.1038/nrd2280 Mechanotransduction stretch-sensitive cation channe Depolarisation of afferent neuro If you want to read more on this look at: Delmas et al 2011 Molecular mechanisms of mechanotransduction  Ions flow through channels, eg. Ca2+ and Na+ enter depolarising the cell, causing action potentials if threshold is reached. https://www.youtube.com/watch?v=OZG8M_ldA1M Action potentials in C- fibres. In response to pinch stimuli in anesthesised rat. Hachisuka et al 2010 Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain Jessica O'Neill, Christina Brock, Anne Estrup Olesen, Trine Andresen, Matias Nilsson and Anthony H Dickenson Annette C. Dolphin, Pharmacological Reviews October 2012, 64 (4) 939-971; DOI: https://doi.org/10.1124/pr.112.006163 Activation of ion channels in free nerve endings can cause action potentials if sufficient depolarisation in the nerve fibre occurs. Action potentials in DRG neuron in culture after application of capsaicin. Koplas et al 1997 Threshold for action potential (activation of Na+ channels)  Nociceptors. Free nerve endings detect stimuli and can fire action potentials. Sensory (including noxious) stimuli arrive in the dorsal horn of the spinal cord. Chemical synapse (glutamate) Secondary neurons Afferent Transduce mechanical energy applied to the skin into sequences of action potentials. Molecular mechanisms of mechanotransduction in mammalian sensory neurons Delmas et al 2011 Dull/aching pain. Slower 0.5-2m/s Non- Myelinated Myelinated http://docjana.com/saltatory- conduction/ Myelin (Shwann cells) Insulates/protects/nourishes fibre. Rapid/saltatory conduction (sharp well localised pain). 5-40m/s  Aδ: mechanosensitive or Ab mechanothermal nociceptors Ad C C fibers: polymodal nociceptors http://thebrain.mcgill.ca/flash/d/d_03/d_03_cl/d_03_cl_dou/d_03_cl_dou.html  Nociceptors are small diameter, slowly conducting (Ad,C), compared with other sensory fibres. Free nerve endings Themistocleous, a. C. et al., 2015. The clinical approach to small fibre neuropathy and painful channelopathy. Practical Neurology, 14(6), pp.368–379.  Peripheral nerve - Fascicle: Bundle of nerve fibers (a few thousands). Remak bundles http://what-when-how.com/acp-medicine/diseases-of-the-peripheral-nervous-system-part-1/ Early perception of sharp pain and a later sensation that is described as having a duller, burning quality. “First and second pain” Carried by different axons (selective block)  How are Harmful Stimuli Detected? Tominaga, M. et al (2003). Molecular mechanisms of  How are Harmful Stimuli Detected? Transcutaneous recordings using microneurography show that there are specialised nerve fibres that detect noxious stimulation Latency (100mm = Velocity 0.1m) 10ms (0.01s) 0.01s, 0.1m 0.1m/0.01s = 10m/s Ad-fibres Ad c 100ms (0.100s) 0.1s, 0.1m 0.1m/0.1s = 1m/s Voltage C-fibres 0 100 200 Latency (ms)  Travelling to the brain, but where exactly are the signals going? There is not a single “pain centre” or “pain nucleus” in the brain. Activity from different brain structures is integrated into a “conscious experience of pain”. The discriminative component: pathways that target the traditional somatosensory areas of cortex, The affective-motivational component is thought to depend on additional cortical and brainstem pathways. (Paleospinothalamic) As is the case of the mechanosensory pathway, information about noxious and thermal stimulation of the face follows a separate route to the thalamus The spinothalamic tract, which carries the sensory modalities of crude touch, pressure, pain and temperature. Nociceptive ascending systems (conscious) Body (and posterior Face (and anterior portion portion of the head) of the head) Pain and temperature: Pain and temperature:  Spinothalamic tract  Trigeminothalamic tract a.k.a. anterolateral system (face, oral) Through the spinal nucleous of the trigeminal complex. The affective–motivational aspect of pain is mediated by separate projections of the anterolateral system to the reticular formation of the midbrain  Nociceptors, Ad Fibres: 'FAST' PAIN Small, thinly myelinated. 10 % sensory nociceptive fibres. Sensations of localised, sharp, pricking pain. Mechanical and thermal stimuli. Conduct at 5-40 m/sec. Afferent portion of the reflex arc (quick reaction to noxious stimuli). A delta fibers carry pricking/sharp pain  Nociceptors, C Fibres: 'SLOW' PAIN Small, unmyelinated fibres. 90% of afferent sensory fibres. Conduct at 0.5-2.0 m/sec. Mechanical thermal, chemical. Potential for long-term sensitisation. Types of pain associated with c-fibres Deep, visceral, dull, diffuse, burning, aching pain Pain prevents tissue damage ✔ Promotes recovery ✔ But: it may reduce survival in a situation when the best thing is to escape  The body has its own analgesic systems. But: Sometimes we know the cause and we just don’t want the pain  Painkillers.  Painkillers: insight into pain modulation. Nitrous oxide Local anesthetic, Adjunct (manage the also known as nerve block cognitive aspect (eg eg. lidocaine, novocain anxiety) diazepam, antidepressants) Non-steroidal anti-inflammatory drugs (NSAIDs) and * Paracetamol: the mechanism of action of paracetamol is not well established, so we won’t Opioid go intoanalgesics detail for this. Ketamine (acute management of very painful conditions: Migraine medications* e.g. after a car crash https://lundbeckfonden.com/en/the-brain-prize to reposition bones). Nociceptors. Free nerve endings detect stimuli and can fire action potentials. Noxious stimuli arrive in the dorsal horn of the spinal cord. Afferent Action potentials are generated by nociceptors and arrive to a first stage of processing in the dorsal horn of the spinal cord.  Painkillers: insight into pain modulation. Local anesthetic, also known as nerve block eg. lidocaine, novocain as dental anesthetic. Inhibit sodium channel molecules directly and prevents the generation and propagation of action potentials.  Tissue Damage and Inflammation Tissue damage results in pain and hyperalgesia Why? Inflammatory chemicals / mediators:  Cause an increase in Neuronal Excitability Three examples of common inflammatory mediators - Prostaglandins - Bradykinin - Substance P This diagram illustrates the complexity of other inflammatory mediators and how they would influence the firing of nociceptive afferents. (You don’t need to learn all the individual names in the diagram!)  Tissue damage and inflammation An example: sunburn Nociceptors are bathed in inflammatory mediators  Increase sensitivity of nociceptors, lower the depolarisation threshold. Painkillers: insight into pain modulation. Non-steroidal anti- inflammatory drugs (NSAIDs) target the production of prostaglandins* by inhibiting the enzyme COX (COX) *Prostaglandins are vasodilators and inhibit the aggregation of platelets. First level of modulation in the processing of nociceptive signals: dorsal horn of spinal cord First order neurons  Second order neurons   First level of modulation in the processing of nociceptive signals: dorsal horn of spinal cord Todd et al 2010, Nature Reviews Neuroscience. es. Substantia gelatinosa layers II and III C fibres go directly to reticular formation (sleep), or limbic areas of the brain (mood, emo First level of modulation at spinal cord (called: segmental controls of spinal origin) See Gate control theory – Blackboard ‘A gating mechanism in the spinal cord (substantia gelatinosa of dorsal horn) can be opened or closed in varying degrees thereby modulating incoming signals before they reach the brain’  Diffuse inhibitory controls induced by nociceptive stimuli (one pain masks another). Brain stem origin. Ascending nociceptors make connections within the brainstem, e.g. in the periaqueductal gray matter. These brain stem structures can return descending signals to inhibit nociceptors. Thus a first pain would mask a second pain. Painkillers: insight into pain modulation. Opioid analgesics The body has its own analgesic system: it uses endogenous opioids. Exogenous opioids (morphine, diamorphine, codeine) are used for the treatment of pain. Descending controls of from the brain associated with psychological factors Hipothalamus dorsolateral tract dorsolateral tract Enkephalin is an endogenous opioid. advanced How does inhibition by enkephalin work? - Pre-synaptically Makes the action potential narrower  limits neurotransmitter release - Post-synaptically  generates an inhibitory postsynaptic potential driving the cell away from the action potential  Some stages of modulation for nociceptive signals: Segmental controls of non-pain peripheral origin (see also gate control theory). Descending pathways Diffuse inhibitory controls induced by nociceptive stimuli (one pain masks another). Brain stem origin. Descending controls of from the brain associated with psychological factors. Endogenous opioids (production depends on complex psychological phenomena, artificial stimulation of the periaqueductal gray produces analgesia).  Referred Pain Pain perceived at a location other than the site of nociception Very few projection neurons specialised for transmission of visceral pain. Cutaneous and visceral nociceptive afferents converge on projection neurons. eg. myocardial (heart) pain (angina) can be felt in the left arm or shoulder. Activation of heart nociceptors leads to activation of projection neurons that signal for left arm pain. Knowledge of the sites where visceral pains are commonly referred to is important in diagnosis. Further definitions, including disease-related Allodynia Pain due to a stimulus that does not normally provoke pain. Neuropathic pain Pain caused by a lesion or disease of the somatosensory nervous system.  Further reading: Purves, Neuroscience http://www.nhs.uk/Conditions/Peripheral-neuropathy/Pages/Treatment.aspx​ https://thebrain.mcgill.ca/ https://www.youtube.com/playlist?list=PLhQlGwSO9- P63_b6RnG6B37A5E5ALLp7c