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Pain and neurotransmitters

Created: 21/4/2006
Updated: 21/3/2006
 
a. Define pain.

An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

Fast and slow pain: fast pain is sharp, well-localized and is conducted via Ad afferent nerve fibres. Slow pain is dull, poorly localized and conducted via C fibres.

Somatic and visceral pain: somatic pain is conducted via spinal nerves and is localized to the site of the stimulus. Visceral pain is conducted via autonomic fibres and localizes to the dermatomal level of the organ innervated where it can produce secondary hyperalgesia. It is provoked by stretch or ischaemia and is not associated with protective reflexes.

Deep and superficial pain: superficial pain is somatic, well-localized and unpleasant. Deep pain may be somatic, but is poorly localized and is associated with nausea, sweating, muscle spasm and blood pressure changes.

Allodynia
  • Pain perceived in response to a stimulus which does not usually cause pain
Analgesia
  • Absence of pain in response to a normally painful stimulus
Anaesthesia dolorosa
  • Pain in an area that is anaesthetic
Causalgia (CRPS II)
  • Sustained burning pain, allodynia and hyperpathia after traumatic nerve injury, often accompanied by vasomotor, sudomotor and trophic changes
Dysaesthesia
  • An unpleasant or painful sensation
Hyperalgesia
  • Increased response to a normally painful stimulus
Hyperaesthesia
  • Increased sensitivity to stimuli
Hyperpathia
  • A painful syndrome with increased reaction to a stimulus, especially a repetitive one, and increased threshold
Neuralgia
  • Pain in the distribution of a nerve
Paraesthesia
  • An abnormal sensation
b. Describe pain mediators and pain pathways and display an appreciation of the gate control theory and the concept of preemptive therapy.

Receptors
  • Mechanosensitive

Respond to mechanical stimuli
Ad conduction (myelinated)

  • Mechanothermal

Mechanical stimuli and temperatures over 43°C
Ad conduction

  • Polymodal

Mechanical, thermal and chemical stimuli (ACh, bradykinin, histamine, PGs, K)
C conduction (unmyelinated)

  • All high threshold
  • Do not show adaption (unlike most receptors)
  • Sensitized by chemical mediators
Dorsal horn transmission
  • Ad fibres synapse in the dorsal horn Rexed laminae I (nociceptor specific) and V (wide dynamic range)
  • C fibres synapse in the dorsal horn laminae I and II (substantia gelatinosa)

Dorsal horn transmission displays long term potentiation resulting from repeat stimuli

  1. Slow depolarizing response to substance P
  2. Enhanced NMDA transmission: activation of NO synthase, c-fos expression, ?dynorphin, ?NGF which induces new neurite growth (Aß ?WDR)
  3. Transmission is sensitized by substance P even while anaesthetized, hence preoperative local and intraoperative opioids for preemptive analgesia

Substantia gelatinosa

  1. Inhibited by Ad and C nociceptive afferents
  2. Stimulated by A??mechanoreceptor afferents and descending pathways
  3. Short inhibitory interneurones project to laminae I and V, inhibiting pain transmission (Gate Control)
  • Spinal motor neurones

Withdrawal reflex
?Guarding

Ascending pathways

  • Contralateral spinothalamic tract

Posterior thalamus produces localization
Medial thalamus produces unpleasant experience and autonomic response
Thalamus projects to somatosensory cortex (SI and II) and cingulate gyrus (emotional response)
Also projects to nucleus reticularis paragigantocellularis

  • Multisynaptic system

Fasciculi proprii and Lissauer’s tracts project to reticular formation and thalamus
Slower transmission

  • Periaqueductal grey matter

Opioid receptors stimulate descending pathways which inhibit transmission in the dorsal horn (transmitter may be serotonin)

  • Hypothalamus
  • Spinoreticular tract (brainstem)

Stimulation of reticular activating system
Thalamic projection

  • Visceral afferents probably both converge on and facilitate transmission in somatic pathways, producing referred pain. Experience influences the site of projection of referred pain (i.e. preferentially to traumatized sites).
Descending pathways

  • Locus ceruleus

Inhibitory descending projection to dorsal horn
Noradrenaline inhibitory neurones

  • Periaqueductal grey matter

Input from cortex, thalamus, hypothalamus
Opioid receptors
Stimulates nucleus raphe magnus

  • Nucleus raphe magnus

Input from periaqueductal grey matter and nucleus reticularis paragigantocellularis
Descending projection in dorsolateral funiculus to dorsal horn
Serotonin and enkephalin inhibitory neurones

Transmitters

  • Glutamate

Primary afferent transmitter
Fast transmission via AMPA ((R,S)a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors & others
 - increase in Na+, K+ conductance
Slow potentiation via NMDA (N-methyl-D-aspartate) receptors
- Ca2+, Mg2+, Na+, K+ channels
NMDA antagonists such as ketamine may prevent the increase Ca2+, NO production, cfos expression, neuropeptide Y release and development of aberrant Aß fibres which activate WDR neurones in response to mechanical stimuli, causing a pain syndrome.

  • Substance P, CGRP and somatostatin

Primary afferent transmitters
Cause slow and prolonged depolarization (LTP) via NK1 and NK2 receptors
Phospholipase C, IP3, DAG --> increase in Ca2+ --> K+ efflux
2° messengers inhibited by some gangliosides
Sensitizes primary nociceptors in the periphery
Activate WDR neurones to respond to all stimuli (Aß mechanoreceptive etc. ---> “pain”)

  • enkephalins, endorphins and dynorphin

Receptors in the periaqueductal grey matter, nucleus reticularis
Paragigantocellularis and other central sites stimulate descending inhibitory
pathways from the nuleus raphe magnus
Opioid receptors are also present in the substantia gelatinosa and may act as presynaptic inhibitors of substance P release
Play a role in placebo analgesia and stress analgesia (antagonized by naloxone)
Role in “resting” state is controversial

  • Serotonin

Strong direct stimulation of nociceptors
Transmitter in descending inhibitory pathways
Inhibits substance P transmission in dorsal horn (mechanism uncertain)

  • Noradrenaline

Inhibitory transmitter at dorsal horn via a2 (clonidine analgesia)
Injured cells may express a-receptors (?pathology)
May stimulate dorsal ganglion afferent fibres directly in reflex sympathetic dystrophy

  • NO

Enhances dorsal column transmission (via c-fos)

  • Bradykinin

Direct stimulation of nociceptors (G-linked receptor)
Stimulates PGE2 release (and possibly other PGs) which potentiates bradykinin response

  • GABA

Inhibitory GABAA receptors on WDR neurones
Presynaptic GABAB inhibition of excitatory neurotransmitter release
GABAergic drugs used in neuropathic pain

  • Glycine

NMDA agonist
Blockers used for specific therapy

  • Capsaicin

Not an endogenous transmitter
Acts on Ca2+ channel linked receptors
Stimulates substance P release acutely
Depletes substance P with repeat use
Destroys C fibres in the newborn

  • Other inhibitory transmitters

Somatostatin, galanin, adenosine, cholecystokinin

 

c. Describe the role in analgesia of a2 agonists, inhalational alagesics, NMDA antagonists, non-steroidal anti-inflammatory drugs, serotonergic agents and activators of adrenergic inhibition (tramadol).

Some sites of action detailed above. Details under specific drugs.

d. Describe and evaluate methods in the assessment and measurement of pain in animal models and patients.

Kindly provided by Dr James Mitchell from his pharmacodynamics series

ArticleDate:20060421
SiteSection: Article
 
   
    
                                            
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