Pain physiology

Pain physiology

1. Pain Physiology R.Srihari

2. Topics for discussion Definitions Physiology of pain Pain pathway Important terminologies

3. Definition Pain: An unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage Nociception : neural response related to potentially tissue damaging stimuli

4. Terminologies for pain dysthesia – experience of abnormal noxious sensation paraesthesia - abnormal nonpainful sensation; hyperpathia - exaggerated pain response to noxious or nonoxious stimuli) allodynia - perception of nonoxious stimuli as painful

5. Hyperalgesia : increased pain response to painful stimuli Hypoalgesia : decreased sensitivity to noxious stimuli Hyperesthesia and Hypoesthesia :increase or decrease, respectively, in sensitivity to nonnoxious stimuli

6. Physiology of Pain Pain transmission: A good way to understand physiology of pain is to follow nociceptive signal pathways from the periphery to the brain, with emphasis on integration and modulation of nociceptive signal at different steps in the CNS

7. Transmission of pain occurs by : Transduction Transmission Perception Modulation For understanding, it can be divided into peripheral transmission and central transmission

8. Peripheral Transmission: Peripheral transmission of pain consists production of electrical signals at the pain nerve endings (Transduction) followed by propagation of those signals through the peripheral nervous system (Transmission) Central Transmission: Includes transmission and perception whereby signals are transmitted from spinal cord to the brain

9. Transduction: Primary sensory structure that accomplishes transduction – nociceptor (free nerve endings sensing heat, mechanical and chemical tissue damage) Several types are described: Mechanoceptors – sense pinch and pin prick Silent nociceptors - sense pain only during inflammation Polymodal mechanothermal receptors- most prevalent and respond to excess pressure, temperature and algogens

10. Transmission: Pain impulses transmitted by 2 fibre systems The presence of 2 pain pathways-explains existence of 2 components of pain: Fast pain(Ad) and Slow pain (C ) Ultimately synapse in spinal cord with second order neurons which send impulse to CNS

11. Perception: From thalamus to somatosensory areas of cerebral cortex( in the post central gyrus ) and superior wall of the sylvian fissure Fibres are also projected to limbic system- anterior cingulate gyrus and insula

12. Modulation: Occurs at different sites: Nociceptor Spinal cord Supraspinal structures This modulation can either inhibit or facilitate pain

13. Peripheral Modulation: Nociceptors and their neurons display sensitization following repeated stimulation Sensitization of nociceptors result in decrease in threshold Increase in frequency response Decrease in response latency Spontaneous firing even after cessation of stimulus Primary hyperalgesia mediated by algogens like histamine, bradykinin , PGE2 and leukotrienes from damaged tissues

14. Secondary hyperalgesia or neurogenic inflammation-  longterm  tissue hypersensitivity beyond area of original injury  within the CNS Repeated recruitment of C- fibres following an injury will cause change in response properties of membranes of secondary neurons Over a period – can cause increase in perceived pain even if intensity of stimulation remains constant This spinal sensitization can persist for minutes, but can also present for hours or even days The prolonged activation of NMDA receptors will induce transcription of rapidly expressed genes (c- fos , c- jun ), resulting in sensitization of nociceptors This neuronal plasticity of the secondary neuron will result in reduced recruitment threshold of secondary neurons in the spinal cord hyperalgesia and allodynia that persist even after healing of injury

15. Central Sensitization: refers to phenomenon where second neuron membrane permeability changes and responds at higher frequency when recruited by nociceptive and non- nociceptive primary input This can facilitate or inhibit pain. The mechanisms of facilitation are as follows: Windup and sensitization of second order neurons Receptive field expansion Hyper excitability of flexion responses Neurochemical mediators of central sensitization sP , CGRP, VIP, Cholecystokinin , angiotensin , galantin , L- aspartate and L-glutamate

16. These substances trigger changes in membrane excitability by interacting with G-protein coupled receptors Activating intracellular second messengers Phorsphorylate substance proteins Leading to increased intracellular calcium concentration Stimulate Nitric oxide synthase and production of NO NO diffuses action of neuron and by action on guanylyl cyclase , NO stimulates formation of cGMP in neighbouring neurons Depending on the expression cGMP - controlled ion channels in target neurons, NO may be excitatory or inhibitory- most cases implicated in development of hyperalgesia and allodynia

17. Inhibitory mechanisms can be either Spinal or Supraspinal Segmental inhibition –consists of activation of large afferent fibres of inhibitory WDR neurons and spinothalamic activity Glycine and GABA –inhibitory neurotransmitters Segmental inhibtion mediated by GABA receptor activity  increases K+ conductance across cell membrane

18. Supraspinal inhibition – occurs whereby several supraspinal structures send fibres down the spinal cord to inhibit pain at the level of the dorsal horn Includes – Periaqueductal Gray, Nucleus Raphe Magnus and Reticular formation Axons from these structures act pre- synaptically on the primary afferent neurons and post synaptically on the second order neurons( interneurones ) These axons utilise monoamines (NA and Serotonin) as neurotransmitters and terminate on nociceptive neurons in spinal cord + spinal inhibitory interneurones (store and release opioids ) Noradrenaline mediates action via alpha 2 receptors Endogeneous opioids via enkephalins and B-endorphins– mainly act presynaptically whereas opiates act postsynaptically

19. Cognitive Modulation: Involves patient’s ability to relate a painful experience to another event

20. Pain Pathway

21. Important terminologies Physical characteristics of nerve fibres : Ab Ad C Diameter 6-12 microns Myelinated 1-5 microns Myelinated 0.2-1 microns Unmyelinated Conduction 33–75 m/s 3–30 m/s 0.5-2.0 m/s Role Light touch Proprioception Temperature Nociception ( mechanical,thermal ) Nociception (mechanical, thermal, chemical)

22. Ab fibres : Besides conduction of non- nociceptive signal, stimulation of Ab fibres will recruit inhibitory interneurones in the substantia gelatinosa of dorsal horn  inhibition nociceptive input at same spinal segment (innocuous stimulus) Ad fibres : Responsible for the first pain sensation, rapid pinprick, sharp and transient sensation C fibres : Represent 3 quarters of the sensory afferent input and are mostly recruited by nociceptive stimulation Responsible for dull aching pain

23. First and Second pain: Conduction velocity between Ad and C fibres can be appreciated when isolating sensation of 1 st and 2 nd pain Following brief nociceptive stimulation- Ad fibres will transmit brief and acute pin-prick like sensation, perceived to be precisely located at he point of stimulation  results in nociceptive withdrawal reflex Following this activity, C fibres will transmit their information with long delay (100ms to 1 s) depending on stimulus location

24. Secondary neurons : can be classified as Nociceptive specific neurons: Respond only to nociceptive stimulation Can be divided into 2 subclasses depending on their recruitment by Ad alone or combination of Ad and C fibres Wide dynamic range neurons: Respond gradually to stimuli from innocuous to nociceptive Their capacity to respond to both nociceptive and innocous stimuli is related to the fact that they have received input from Ad, C and Ab fibres Receptive field is dynamic Changes in receptive field, membrane permeability to ion exchange and discharge frequency of these neurons all suggest  substantial role in chronicity of pain

25. Temporal Summation: Good illustration of importance of signal conduction in Ad and C fibres Here, pain perception is compared with repeated stimulations at same intensity but different rates High frequency of stimulation will produce temporal summation of C- fibre activity as a result of relatively slow conductance of these fibres Resulting in increased perceived intensity of second pain

26. Spatial Summation: Stimulation of a large territory will recruit more nociceptors than when a small area is stimulated Results in more intense pain perception However increasing surface area that is stimulated recruits both excitatory and inhibitory mechanisms

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