Introduction to Pain - Dr Safiya Robinson 24-25.pptx

Year 1 BDS and DTH Life Sciences 2023-2024 An Introduction to Pain Dr Safiya Robinson (with some slides compliments of Dr Yen Lin) [email protected] Year 1 BDS & DTH Learning Objectives To consider the role of the dorsal root ganglia and events modulating sensory input in the dorsal hor...

Year 1 BDS and DTH Life Sciences 2023-2024 An Introduction to Pain Dr Safiya Robinson (with some slides compliments of Dr Yen Lin) [email protected] Year 1 BDS & DTH Learning Objectives To consider the role of the dorsal root ganglia and events modulating sensory input in the dorsal horn, introducing the ‘gate theory’ as a way of explaining how sensory input can be modulated at the level of the spinal cord To provide an overview understanding of the ascending pathways by which nociceptive information is transmitted and modulated en-route to the sensory cortex To provide a baseline for comparison pain transmission in the trigeminal system What is pain? Pain is a perception derived from a particular stimulus or pattern of stimuli. Pain is one of the body’s ways of altering us that something is wrong. Pain is not the stimulus itself, instead it is the physiological perception. Pain is subjective Nociceptor is a sensory receptor that responds to stimuli that cause pain. What Types of Stimuli May Result in Pain? Mechanical ? Therma l? Chemical? Radiatio n? Pain is not just abstract concept of Philosophy Definition from International Association for Study of Pain. http://www.iasp-pain.org/ ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ Pain is conscious experience Pain is always subjective emotional experience and can only be described in terms of human consciousness and experience As with all sensory experience there is no way of being certain that one persons experience of pain is same as another’s More facts about pain Nociceptors are sensory receptors that respond to painful stimuli. These receptors especially common in superficial portions of the skin, joint capsules, around the walls of blood vessels etc. Pain receptors are free nerve endings with large receptive fields - which means that it is often difficult to determine the source of painful sensations. Different nociceptors are sensitive to temperature, mechanical damage and chemical stimuli, and strong stimuli can impact all 3 of them. More facts about pain There are 2 types of afferent nerve axons (towards the brain) that carry painful stimuli. Type A delta and C fibers. A fibers are myelinated, and they carry fast/prickling pain - which can allow localisation. Type C are unmyelinated, and carry slow - aching pain which tends to be poorly localised. These receptors respond specifically to noxious or potentially damaging stimuli They are discrete group and are referred to as nociceptors These receptors are physiologically distinct from those which respond to low threshold, innocuous stimuli such as gentle touch and warm or cold sensations Histologically they usually take form of free nerve endings and are Pain pathways Pain Pathways Transduction – stimulus activates system Transmission – route the signal takes Modulation – up or down Perception - Pain Pathways Transduction – Nociceptors in skin, muscle, bone, teeth. It is chemically mediated – where mediators selectively change the permeability of the receptor leading to action potential. Transmission – via peripheral nerves up spinal cord (dorsal horn), to the mid brain and into the sensory cortex Modulation – up or down Perception - Activation Of Somatic Nociceptors Transduction Is....... Chemically mediated, many intra and extracellular mediators, e.g. Bradykinin, histamine, serotonin, 5HT, potassium ions and many others Mediators act by selectively changing membrane permeability of receptor and producing 'generator potential’ Mechanisms by which these are initiated are highly complex and much more diverse than those responsible for action potentials in nerve axons Likely that calcium ions play significant role in production of generator potentials Nociceptive Pathways – An Overview Transmission..... OK, we now have signal and rough idea of map, so which way does it go? Two routes of onwards travel are possible:Neospinothalamic tract Evolutionary 'newer' pathway – concerned with 'fast' pain from skin receptors, mediated by thin, myelinated A delta fibres Paleospinothalamic tract Evolutionary ‘older' pathway – mainly concerned with transmission from 'slow' pain receptors in deep layers of skin, from deeper structures e.g. muscles, joints etc., and from viscera, mediated mainly by non-myelinated 'C' fibres, although there is some Ad Destinations Gate control theory The tale of 2 nails. Gate Control Theory Biopsychosocial model of pain Described physiological mechanism by which psychological factors can affect experience of pain Gate Control Upon injury, pain messages originate in nerves associated with damaged tissue and flow along peripheral nerves to spinal cord and on up to brain Before they reach brain, pain messages encounter “nerve gates” in spinal cord that open or close depending upon number of factors (including instructions coming down from brain) When gates are open, pain messages “get through” easily and pain can be intense When gates close, pain messages are prevented from reaching brain and may not even be experienced Open Gate Conditions that Open Gate Physical conditions Extent of injury Inappropriate activity level Emotional conditions Anxiety or worry Tension Depression Mental Conditions Focusing on pain Boredom Close Gate Conditions That Close Gate Physical conditions Medications Counter stimulation (e.g., heat, massage) Emotional conditions Positive emotions Relaxation, Rest (not watching TV or drinking) Mental conditions Intense concentration or distraction Involvement and interest in life activities Benefits And Problems Of Pain Pain sensation is protective mechanism to minimise tissue damage step on something sharp Reflex reaction to remove limbs from source of danger touch something hot poor sleeping posturePain prompts adjusting position to prevent musculoskeletal damage over-vigorous exercise Pain prompts exercise cessation preventing joint/muscle damage damaged muscle broken bone skin wound Hyperalgesia (increased sensitivity of nociceptive neurons to pain stimuli) leads to guarding of damaged area and improved likely hood of healing Pathological pain Prolonged hyperalgesia resulting from central sensitization of second order interneuron and peripheral sensitization of the primary nociceptor results in debilitating persistent pain e.g. Osteoarthritis Interstitial cystitis Pancreatitis Nerve damage can lead to prolonged, severe neuropathic pain that doesn’t respond to analgesics Modulation of Pain Most analgesia from activity in Periaqueductal grey, periventricular areas, nucleus raphe magnus and Locus coeruleus Can originate in higher centres of brain (Post central gyrus Multi-synaptic Ipsilateral, dorsal descending pathway Neurotransmitters involved include enkephalin, serotonin and noradrenaline (LC) Bodies In-built Mechanisms For Reducing Intensity Of Pain Perception (i) Pain Gating In Dorsal Horn dorsal column c-fibre nociceptor synapses with projection interneuron in dorsal horn Painful stimulus sends AP along c-fibre dorsal horn Glutamate is released from c-fibre terminal and activates interneuron sending an AP to thalamus Nociceptor also has branch that innervates inhibitory interneuron in dorsal horn ventral horn dorsal horn Aβ low threshold mechanoreceptor Low threshold mechanoreceptors (LTMs) often branch in dorsal horn to synapse with inhibitory interneurons dorsal column + - c-fibre nociceptor - + to spinothalamic tract Activation of c-fibre prevents inhibitory interneuron from firing When LTM fires AP it activates inhibitory interneuron which in turn releases neurotransmitter GABA GABA activates GABA receptors on projection neuron Cl- entry and hyperpolarization reducing sensitivity of projection neuron to activation Bodies In-built Mechanisms For Modulating Intensity Of Pain Perception (ii) Descending Regulation thalamo-cortical Main descending control neuron pathway starts in PAG Neurons from PAG project to Raphe thalamus nuclei in medulla Neurons from Raphe Periaquaductal nuclei project gray matter project to dorsal horn Raphe nuclei sensory cortex forebrain midbrain spinothalamic tract Prima ry DRG neuro n medulla spinal cord nucleus proprius (dorsal horn) containing cell body of decussation Bodies In-built Mechanisms For Modulating Intensity Of Pain Perception (iii) Endogenous Opioids Endogenous opioids are small peptides that are produced by body (mainly the nervous system and in particular hypothalamus/pituitary) in response to physical exertion, pain, excitement and sexual pleasure Endogenous opioids have several actions in nervous system one of which is analgesia Analgesic endogenous opioids product of Pro-opiomelanocortin (POMC) gene Endorphins Met enkephalin (Tyr-Gly-Gly-Phe-Met) product of (POMC) and/or enkephalin gene Leu enkephalin (Tyr-Gly-Gly-Phe-Leu) product of prodynorphin and/or enkephalin gene Dynorphins A and B product of prodynorphin gene Nociceptin product of pronociceptin gene Opioid Receptors Opioid receptors are G-protein coupled cell membrane receptors that on activation alter excitability of neurons that express them Opioid receptors expressed by: Mu opioid receptors activated by endorphins, Primary nociceptors Kappa opioid receptors enkephalins and dynorphins PAG neurons Delta opioid receptors Raphe “off” projection neurons only activated by nociceptin ORL-1 Somatic Pain, Summary… Superficial: From skin Includes ‘fast’ pain. This is sharp, well localised and fades quickly – from myelinated Aδ mechanoreceptive nociceptors – avoidance reactions. No associated autonomic responses Often followed by ‘delayed’ pain. Dull burning sensation, less well localised and much slower to fade. Tends to indicate tissue damage. Often associated with autonomic responses Structures Responsible For Perception Of Pain Thalamus – essential for perception of pain. Stimulation of thalamic nuclei can result in intense pain Interactions between thalamus and reticular formation are responsible for arousal and origin of many of autonomic responses associated with chronic pain – explain why it is difficult to sleep when suffering from severe pain Sensory cortex. Stimulation of this results in weak pain Loss of connection between cortical areas receiving nociceptive inputs and thalamus does not eliminate pain sensation Important for interpretation of qualities of pain sensation Responses To Pain Physiological – Result of activation of neural pathways from receptors that can result in perception of pain Autonomic responses to pain Affective responses (affective is defined as: ‘general psychological state of an individual, including but not limited to emotions and mood, within given situation’) to pain – differ with circumstances and patient and are often of more interest and relevance to patient and clinician than physiological ones Note Body’s Normal Responses To Pain Are Learned… If experiences are missed in early childhood appropriate responses are difficult to learn later Congenital insensitivity to pain – either absence of all reactions to noxious stimuli, or missing Aδ and Cfibre afferents (possibly without associated spinal tracts or nuclei) Take Home Message - How We Are ‘Wired Up’...... We envisage CNS 'wiring' like this...... Reality is more like this... Summary Pain may be (1) cutaneous (2) somatic or (3) visceral At its most simplistic there are three neurones on afferent pathway from periphery to cortex termed 1st, 2nd and 3rd order neurones 1st order neurones are (a) faster myelinated Aβ and Aδ fibres carrying sharp pain or (b) slow unmyelinated C fibres which carry dull, poorly localised pain Cell bodies of 1st order neurones are in dorsal root ganglia (DRG) and relay in the dorsal horn of spinal cord Signals passing to 2nd order neurones are modulated in spinal cord by (1) balance of inputs from Aβ and Aδ and C fibres and activity in fibres descending from higher centres. This is basis of ‘Gate’ theory. The Trigemin al System Learning Objectives To review the passage of afferent pain impulses to the dorsal horn of the spinal cord and their regulation, covered in the ‘Intro to Pain’ plenary To consider the anatomical similarities and differences between afferent impulses passing to the dorsal horn of the spinal cord and those passing to the brain stem in the Trigeminal nerve To site this discussion in the context of afferent impulses from the teeth To emphasise that, although there are anatomical differences, the principles of the ‘Gate Theory’ hold true for the Trigeminal system Trigeminal Nerve Anatomy, whilst different is broadly analogous to that of peripheral nervous system, has certain unique features that can influence pathological conditions that occur within its’ distribution Processing of sensory information is carried out in similar regions of mid brain and sensory cortex Unique structures (e.g. teeth) innervated by TN, result in unique sensory characteristics Peripheral Anatomy Of Trigeminal Nerve Arises from Pons just above medulla and is mixed, with both afferent and efferent fibres, but afferent predominate Its ganglion (semi-lunar or trigeminal ganglion) is equivalent of dorsal root ganglion Splits shortly after ganglion into three branches, Ophthalmic, maxillary and mandibular divisions Nociceptive (Aδ and C fibre) inputs cross to spinothalamic (now trigeminothalamic) tract and ascend via medulla and pons to ventroposterior nuclei of brainstem and onwards to cortex Vc Branches – A Survival Guide Fibres Carrying Afferent Impulses From Oro-Facial Tissues Trigeminal Nerve Broadly analogous to spinal nerves Transmits to similar areas in reticular formation, thalamus and sensory cortex Does have several unique features (anatomical) Note there is no ‘normal’ sensory perception from within tooth pulp Localisation of Pain Very precise from areas of skin surface (via convergence with tactile stimuli) Less precise from deeper skin layers Variable precision in different sites Vague from deeper structures (e.g. muscles and joints – diffuse regional convergence) Frequency ‘mis-placed’ from viscera Convergence occurs from different spinal segments, so can be wildly inaccurate, but regions are fairly consistent – ‘Head’s zones’ Can localise quite well from periodontal tissues Wildly inaccurate from within teeth, but always to correct side of midline Examples Include: Lower back pain (sciatica) ‘Slipped’ disc Toothache - Often form of projected pain Pain From Teeth No natural non-nociceptive conscious perception from teeth (although can artificially stimulate electrically to give ‘pre-pain’ sensation) Very poorly localised – suggesting wide convergence with somatic inputs Usually severe Characteristics of chronic and visceral pain, even in acute situation (affective effects and some autonomic responses) Frequently either projected or referred PROJECTED Pain Projected pain – felt from an area served by affected nerve, as well as site from which noxious stimulus originates as result of convergence.. Referred Pain A little different, this time pain may be felt in remote location different from that served by nerve fibres from associated nociceptors Visceral pain is good example: Toothache Is Often Referred….. Pain frequently refers between upper and lower teeth Pain often refers between different divisions of trigeminal nerve Referred pain DOES NOT cross midline Most Dental Pain Is Acute Provided it is treated appropriately…. However, some important causes of chronic ‘dental’ pain include: Atypical facial pain Trigeminal neuralgia Chronic Pain In clinical terms relates to conditions where pain persists more six months Typically includes arthritis, cancer, back pain, fibromyalgia, even headache Can produce other physical manifestations, including loss of appetite, muscle tension, reduced mobility and muscle tension Produces emotional effects, such as depression, fear of recurrence, anxiety and anger Physiologically Chronic Pain… Irrespective of origin, causes unknown changes in CNS that favour their occurrence – Tends to get worse with time not better. In other words tends to sensitisation rather than de-sensitisation Undesirable learning process…. Can result in small external (or even spontaneous internal fluctuations in neuronal excitability) being sufficient to produce full extent of pain In other words dissociation of external pain stimulus The trigeminal nerve and the gate theory Trigeminal nerve and the gate theory Remember that the gate theory is a biopsychosocial model of pain While the gate theory considers the presence of gates in the spinal cord the principles hold true for the trigeminal nerve – even though it does not synapse via the spinal cord. Nucleus caudalis acts as a gate for the sensory input from the trigeminal nerve If that input is pain, it can be modified within the nucleus caudalis either by inhibitory or stimulatory influences. So similar to pain in other parts of the body, facial pain from the trigeminal can be modulated by emotions, anxiety, worry etc. Summary Pain in trigeminal region is broadly analogous to that from periphery Central structures involved are similar Differing anatomy and structures innervated give rise to certain unusual pain characteristics Toothache is disproportionately severe pain Summary Pain from teeth and oral cavity is carried by (a) faster myelinated Aβ and Aδ fibres carrying sharp pain or (b) slow unmyelinated C fibres Again, at its most simple there are three neurones on afferent pathway from periphery to cortex termed 1st, 2nd and 3rd order neurones Cell bodies of 1st order neurones are in Trigeminal ganglion. They then relay in sensory nuclei within Spinal Tract of Trigeminal nerve, an elongated structure extending length of the brainstem and into upper spinal cord Signals passing to 2nd order neurones are modulated in this sensory nucleus by (1) balance of inputs from Aβ and Aδ, and C fibres and (2) activity in fibres descending from higher centres. This is site of ‘Gate’ Pain pathways from teeth and oral cavity are thus analogous to those from skin Year 1 BDS & DTH Recommended Reading Wall P. D., Melzack R (1962) "On nature of cutaneous sensory mechanisms," Brain. V85. pg 331. Melzack R., Wall P. D. (1965) "Pain mechanisms: A new theory," Science, V150. pg 171. Cadden S. W., Orchardson R. (2001) The Neural Mechanisms of Oral and Facial Pain. Dental Update. V28. pp 359-367. Practice Questions 1. Where would a second-order nociceptive neurone from the right lower limb normally synapse onto? A. B. C. D. Right ventral posterolateral nucleus of the thalamus Left ventral posterolateral nucleus of the thalamus Left primary somatosensory cortex Right anterior white commissure of the spinal cord Practice Questions 2. Where do fibres C synapse within the spinal cord? A. B. C. D. Substantia gelatinosa Rexed laminae I Ventral posterolateral nucleus of the thalamus Rexed laminae IV Practice Questions 3. What evolutionary changes would increase the sensitivity of mouse forepaws? A. Increasing the size of the receptive fields and receptor density in the forepaws; with the corresponding increase in the forepaw primary somatosensory cortex. B. Increasing the size of the receptive fields but reducing the receptor density in the forepaws; with the corresponding reduction in the forepaw primary somatosensory cortex. C. Reducing the size of the receptive fields but increasing the receptor density in the forepaws; with the corresponding increase in the forepaw primary somatosensory cortex D. Reducing the size of the receptive fields but reducing the receptor density in the forepaws; with the corresponding increase in the forepaw primary somatosensory cortex. Recommended Reading Fitzgerald's clinical neuroanatomy and neuroscience. E. Mtui. 2016. 7th Ed. Wall P. D., Melzack R (1962) "On nature of cutaneous sensory mechanisms," Brain. V85. pg 331. Melzack R., Wall P. D. (1965) "Pain mechanisms: A new theory," Science, V150. pg 171. Cadden S. W., Orchardson R. (2001) The Neural Mechanisms of Oral and Facial Pain. Dental Update. V28. pp 359-367. Thank you Any Questions? [email protected]