#14111 - Pain - Neuroscience 1

Nociception

Definitions

1. Nociception: Detection of tissue damage by specialised transducers connected to A delta and C fibres

2. 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 analgesia- E.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, histamine-

this 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...