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Pain Notes

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05/01/2016 Nociception Definitions i) Nociception: Detection of tissue damage by specialised transducers connected to A delta and C fibres ii) Pain: Subjective response of the individual to nociceptive input to the brain and may be totally unrelated to the actual physical parameters of intensity and duration of the stimulus Pain: Unpleasant physical or emotional sensation in response to tissue damage or the potential for tissue damage
-Body's way of alerting oneself to danger to prevent further damage , protect the injured part while it heals and withdraw from dangerous situations
-Pain is the most common symptom that patients present to their doctor- so understanding it is crucial to improve the quality of life of patients Classification
-Pain classified - severity, location, duration
-Severity: Pain is highly subjective so difficult to treat- only assessment of intensity of pain is from the patient - rating from 0-10
-How much pain experienced also depends on context (pain beliefs, expectation, placebo), cognitive set (hypervigilance, attention, distraction, catastrophizing), chemical and structure (Neurodegenration, metabolic, maladaptive plastiticty)
-Location of pain- based on body part/ region - visceral pain (organs), deep somatic pain (muscles, fascia), superficial somatic pain (cutaneous/subcutaneous)
-Visceral pain- diffuse and can't be pinpointed to specific location
-Somatic pain is localised and specific
-Duration: Acute pain- specific aetiology, so can be treated easily, Chronic pain (persists for more than 3 months)- back pain, arthritis is often treated symptomatically because it can't be treated as easily Persistent pain: subdivided into Nociceptive and neuropathic, Nociceptive pain results from activation of nociceptors in skin, soft tissue Neuropathic pain: Damge of nerves/ neural tissue itself rather than tissue the nerve is supplying, often burning or electric sensation, syndromes of reflex sympathetic dystrophy, post herpetic neuralgia - MS- not peripheral activation of nociceptors Nociceptors
- Nociception - ability of the body to perceive harmful stimuli in periphery and transmit these signals to the CNS to create experience of pain
-Nociceptors- free nerve endings of primary sensory afferents which have cell bodies in dorsal root/ trigerminal ganglia
-Free nerve endings cover a large area, poor localisation of pain
-3 broad types:

-Thermal- respond to temperature, extreme heat (>45) and extreme cold (<5)
-Mechanical- respond to pressure
-Polymodal- high intensity mechanical, chemical or thermal stimuli
-Thermal and mechanical stimuli are carried by Aδ fibres (conduction velocity 5-30m/s) - myelinated fibres- so stimulus is sensed immediately
-Type 1 Adelta nociceptors/ high threshold mechanoreceptors- respond to mechanical, also sensitive to high >50 degrees temperature - like other classes of nociceptors these cells sensitise to both mechanical and thermal stimuli in presence of tissue injury or inflammation
-Type 2 Adelta nociceptors respond to noxious thermal stimuli Preferentially to mechanical stimuli
-C fiber nociceptors- polymodal- larger, unmyelinated slower- populations of neurons responding to either heat, mechanical or cold nociceptive stimuli. Some C fiber nociceptors are sensitive to heat and mechanical stimuli (CMH nociceptors) whereas others are referred to as silent /sleeping nociceptors- develop sensitivity to heat and chemical stimuli in presence of injury or inflammation
-C fibres innervating the viscera are notable in that they respond to non-injurious stimuli such as stretching of hollow organs while those fibers innervating teeth are responsive to nearly any intensity stimulus to elicit sensations of pain
-So when painful stimulus is applied- immediate sharp pain is due to Aδ fibres, persistent feeling that lasts even after the stimulus is removed- C fibres- more diffuse, dull Visceral nociceptors/ Silent nociceptors
-Found in the viscera- not normally activated by noxious stimuli but instead inflammation C fibres- silent/ dormant
-Few nociceptive fibres innervating viscera- show lot of divergence so the pain presented is diffuse
-Threshold for firing is high, but is reduced massively during infllamtory mediators
-Visceral bloating, GIT cramp, appendicitis, cardiac ischaemia
-Afferent fibres transmit visceral sensory information traven in nerves of sympathetic and more commonly parasympathetic system
-Cardiac general visceral sensory pain fibres follow sympathetitcs back to the spinal cord, cell bodies located in thorasic dorsal root of ganglia- so CNS perceives pain from heart coming from somatic portion of body supplied by thoracic spinal cord segments 1-4. Convergence of information from cutaneous pain sensation axons and visceral pain-Heart- left chest, shoulder, upper left arm referred pain
-Fore gut: T5-T9, Epigastric reigon
-Midgut- periumbilical region via lesser planchnic nerves (T10, T11), only when parietal peritoneum (somatic) over appendix doess pain localise over the right iliac fossa

-Hindgut: suprapubic region (T12) via least splanchnic nerves Molecular level of nociceptors Thermal nociceptors
-C fibres exhibit heat evoked membrane currents with a moderate threshold of 45 degrees
-Type 1 Adelta nocicpetors- respond to a high threshold of 55 degrees
-Thermal nociceptors and chemical nociceptors - TRPV1 channel- non selective cation channel- opens at high temperature/ binding of various ligands such as capsaicin (active ingredient in chillies)
-The capsaicin shifts the sensitivity to the TRPV1 channels to a lower temperature
-Depolarisation from this channel opening depolarises the nerve ending and causes sensation of pain due to heat/ due to application of chilli powder Analgesic drugs: can be both agonists and antagonists - capsaicin based creams on market offer pain relief by first causing light burning sensation but lead to desnensitisation of the receptor- so reduce activity of it
-Antagonists of channel: Capsazepine - blocks activity of TRPV channels- so reduces firing rate of these neurons
-variety of TRP channels in nociceptors throught to underlie perception of a wide range of temperatures from extreme cold to intense heat- TRPV2 channel- Aδ Fibre terminals and is activated by very high temperatures, TRPM8- activated by low temperatures and by chemicals-menthol
-There is a debate that TRPA1 detects noxious cold stimuli
-Xenopus oocytes are injected with mRNA encoding transient receptor potential channels. Electrophysiological recordings from oocytes reveal thermosensitivity of channels. Temperature at which a specific TRP channel is activated is shown by downward deflection of recording
-ASICs respond to low pH
-Mas related G protein coupled receptor family- activated by peptide ligands and serve o sensitise nociceptors to other chemicals released in their local environment
-MDEC/ DRASIC/ TREK-1 detect high pressure
-Nociceptors also selectively express tetrodotoxin resistant Na+ channels
-One Na+ channel: SCN9A- key role in perception of pain in humans
-Mutations in SCN9A channel- voltage gated sodium channel which is expressed in high levels in nociceptive neurons- mutations cause production of truncated, dysfunctional channel-so prevent transmission of impulses from the nociceptors
-Very serious condition- children affected by this condition can't feel pain-so are likely to cause permanent damage without relasing

-Second class of mutations in SCN9A gene- Na V 1.7 channel changes the inactivation kinetics of this channel- Paroxysmal extreme pain disorder- rectal, ocular, submandibular pain Sensitivity to pain
-Congenital insensitivity to pain - cause varies
-Excess release of endorphins in the brain which suppress the response to pain
-Physiologically pain is modulated so that in high stress situations- there is some analgesiaE.g athletes/ soldiers don't feel the full extent of their injuries until the battle is over
-Uncontrolled activation of nociceptors- Allodynia + Hyperalgsia
-Hyperalgesia: exaggerated response to noxious stimuli- most people report persistence in the absence of sensory stimulation
-allodynia: feel pain in response to stimuli that are normally innocuous- by a light stroking of sunburned skin, by arthritis Peripheral component of Hyperalgesia- primary hyperalgesia
-Peripheral sensitisation- reduction in threshold+ increase in responsiveness of peripheral ends of nociceptors found at sites of tissue damage and inflammation-- caused by chemicals released from damaged cells that accumulate at site of tissue injury- peptides, proteins such as bradykinin, Substance P, nerve growth factor, ATP, histaminethis may be physiological and temporary- to prevent further injury to an infected/inflamed area below
-E.g change in heat sensitivity after a sunburn-when normally warm stimulus such as a shower feels burning hot in sunburned areas-mechanical thresholds for pain are lowered at sites of burns- also found the mechanical hyperalgesia-larger than area of flare
-Sensitisation-arises due to action of inflammatory mediators a) Bradykinin
-proteolytic cleavage of active kinins from precursor protein in plasma-Bradykinin-occurs following tissue injury-to show that it is a contributor to pain hypersensitivity-injection of bradykinin into human skin produces dose dependent pain and heat hyperalgesia-this shows bradykinin can exite nociceptors and sensitise their response to heat acts by combining with specific GPCR- B1, B2 nociceptive neurons:
- B2 receptors are coupled to activation of PLC(B)-this catalyses breakdown of PIP2 to IP3-this causes rise in Ca2+- release of DAG-this activates- protein kinaes C ε
isoform- this enhances heat activated current through phosphorylates TRPVI and facilitates TRPVI
-Another mechanism involved in bradykinin induced acute sensitisation of TRPV1hydrolysis of PIP2 by PLC- sensitises channel by relieving TRPV1 from PIP2 inhibition
-Bradykinin also is able to activate the TRPV1 channels directly-based on the observation that bradykinin evoked action potentials were reduced by TRPV1 antagonist capsazepine

-As number of bradykinin induced action potentials in C fibres reduced by lipoxygenase inhibitors-suggests the lipoxygenase products may be involved in this process
-Activation of PLA2 induces mobilisation of Arachidonic acid and generation via the lipoxygenase pathway of 12-HPETE-shown to activate TRPV1 directly
-Also acts on B2 receptors- but bradykinin is converted in tissues by removal of terminal arginine residue to des-Arg Bradykinin- selectively acts on B1 receptors. B1 receptors expressed at low levels but up-regulated in inflamed tissues
-Transgenic KO lacking either type of receptor- reduced inflammatory hyperalgesia Prostaglandins:
-Prostaglandins are another inflammatory mediator-produced mainly by the activation of COX-2 enzymes-upregulated during inflammation
-Prostanoid interact with GPCR- three of these receptors sensitise primary afferent fibresprostaglandin E2 receptors EP1 and EP2 and prostaglanding I2/prostacyclin receptor IPinduce phosphorylation of ion channels which show increased sensitivity to other agentsPKC dependent pathway and Camp/PKA signalling cascade
-Phosphorylation promotes the opening of the vanilloid receptors, calcium channels, voltage dependent Na+ channels, closure of K channels-these increase membrane sensitivity to depoalrisatin- so a smaller stimulus is needed to reach threshold
-Prostaglandins also function as 2nd messengers in potentiation of TRPV1 by other inflammatory mediators such as glutamate-contribute to the development of inflammatory hyperalgesia through group 1 metabotropic glutamate receptors
-These receptors are coupled to PLC pathway-activates PKC downstream-the PKC pathway also leads to the activation of cyclooxygenases. PLC generates lipid messengers such as arachidonic acid-COX metabolises enzymes into prostaglandins-this activates the PKA pathway through prostaglandin receptors
-Analgesic effects of NSAIDs- inhibit prostaglandin synthesis-blocking enzyme Cyclooxygenase 2- normally form prostaglandins -aspirin, ibuprofen
-Acetaminophen- analgesic effects- selective inhibition of COX3 ATP:
-Released from damaged tissues- ATP-produces pain by directly activating nociceptors and induces hyperalgesia by sensitisation of nociceptors to other noxious stimuli
-Two types of ATP receptors expressed on nociceptive neurns-ionotropic P2X and metabotropic P2Y receptors
-Acting via - P2X3 receptors- ligand gated ion channel- selectively expressed by these neurons- down regulation of these receptors by antisense DNA technology reduces inflammatory pain
-P2Y play important role in ATP induced sensitation of TRPV1- as in TRPV1 KO mice, extracellular ATP fails to induce thermal hyperalgesia-patch clamp experiments also confirm that extracellular ATP enhance TRPV1 dependent capsaicin and

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