J.M. Spinal Processing Flashcards
Difference between: pinprick, clinical inflammatory, clinical neuropathic pain
Pin-prick pain (physiological) doesn’t hurt in surrounding uninjured tissue, has appropriate stimulus-response relationship, no spontaneous pain (pain in absence of peripheral tissue stimulation)
Clinical: inflammatory pain e.g. acute trauma & tissue injury or surgery (fracture/burn)- whole hand not just burn area that hurts, altered stimulus-response relationship (exaggerated pain response to stimuli that would normally be painful, hyperalgesia) stimulus such as touch can elicit pain - misinterpreted as painful stimulus (allodynia)
Clinical neuropathic pain
- Persistent phantom pain from stump/amputated limb, thought to be due to damage to nervous tissue itself
Altered stimulus-response relationship (exaggerated responses) and spontaneous pain
Changes in clinical pain (hyperalgesia etc) means effective analgesia more difficult to treat: 40% in Europe have chronic pain condition, <50% get meaningful treatment
How do clinical phenoma affect stimulus response curve?
Normal sigmoid curve - stimulus/response relationship
Hyperalgesia = leftward shift (would see this with capsaicin)
Allodynia = vertical line between the start normal curve and where it meets the hyperalegsia line = area to the left of this line = allodynia
What is the function of normal nociception and the function of sensitisation?
Nociception = Protective, Withdrawal response, aversive experience: complex behavioural responses (avoid doing it again)
Peripheral and central sensitisation =
- Heightened alertness
- Adaptive (at least in the short term)- teaches you not to use injured body part, allows tissue healing
In the absence of ongoing tissue injury return of sensitivity to baseline overtime
What is central sensitisation?
- IASP: Enhanced responsiveness of nociceptive neurons in the CNS to their normal afferent input
Change in properties of CNS neurons - CNS alters how it responds to inputs: pain no longer coupled to intensity/duration of noxious stimulus → exaggerated pain response
- It co-opts with novel nociceptive pathways so that stimuli such as touch start to elicit pain
- Start to get hypersensitivity in non-inflamed tissue (secondary hyperalgesia)
- Often thought to be occurring in spinal cord, but also occurs in higher brain centres (but less is understood about these mechanisms)
What did Woolfe provide evidence for: central or peripheral mechanism in post-injury pain hypersensitivity?
Woolfe 1983: CENTRAL component of post-injury pain hypersensitivity
Recording APs (withdrawal response) from biceps femoris: 28 single a-motor neurons in DECEREBRATE rats: before injury: had low/absent spontaneous activity and high threshold cutaneous mechanoreceptive field (also sig less activity in CL limb than IL limb)
After peripheral injury: spontaneous activity increased & both ipsilateral & CONTRALATERAL limb showed reduced threshold to withdrawal from both Von Frey Hair mechanical stimulus and from noxious heat stimulus. (Increased AP activity). Cutaneous receptive fields also increased by 72% in area.
6 single flexor efferents
?? need to review this don’t get it
*LA injected to Ipsilateral foot: complete sensory block of foot & injury site: could still elicit withdrawal from CL foot - if it was a peripheral change, would expect LA to block the alpha motor neuron activity
Still getting withdrawal when stimulate CL foot, so must be central sensitisation
Once animals were sensitised, stroking toe produced withdrawal (usually innocuous)
Co-opting of novel nociceptive pathways: another reason that it is a central mediating effect
- NOXIOUS HEAT STIMULATION activated C fibres and induced CENTRAL PLASTICITY of the nociceptive system
- NOCICEPTIVE system capable of responding to stimuli OUTSIDE the area of injury & responded to low threshold afferents
Treede & Magerl: how did they investigate relative contribution of A and C fibres to induction of central sensitisation?
Treede and Magerl 2000
- Intradermal capsaicin injection to back of hand excites polymodal A & C fibre nociceptors & some specific chemoreceptors (induces central sensitisation without tissue damage: widely used model)
Equally painful with/without complete A fibre block (weight on string around wrist: ischaemic block of A-delta, but not C) - side with/without block had equal pain ratings
- Suggests excitation of A fibres has little contribution to pain elicited by injection, therefore C fibres important in the pain elicited by capsaicin?
After releasing nerve block, tested magnitude of secondary hyperalgesia 30 mins after the capsaicin injection using punctate mechanical stimuli: equal hyperalgesia/pain between side that initially had nerve block and control side
* again A fibres not important in development of secondary hyperalgesia
However: DURING A delta block, hyperalgesia to capsaicin is significantly reduced: whereas without the block, there is hyperalegsia to the capsaicin
Suggests A fibres important in MEDIATING secondary hyperalgesia (but NOT induction)
Model proposed for central sensitisation - role of C fibres?
C FIBRE CHEMOSENSITIVE input into spinal cord causes HETEROSYNAPTIC FACILITATION of the DORSAL HORN fibres
(C polymodals not facilitative, just has normal transmission, but C chemosensitives are facilitative)
This means α FIBRE LOW THRESHOLD MECHANORECEPTORS (LTM), and α fibre NOCICEPTORS, are FACILITATED at dorsal horn, leading to SECONDARY HYPERALGESIA & ALLODYNIA
-C fibre input drives heterosynaptic facilitation, input of αδ NOCICEPTORS and A FIBRE LTMs is FACILITATED by upregulation of dorsal horn neurons
What changes occur to dorsal horn neurons with central sensitisation?
- Increased spontaneous activity
- Reduction in threshold for activation by peripheral stimuli
- Increased responsiveness to suprathreshold stimulation
- Enlargement of receptive fields
- Switch from nociceptor-specific (NS) to wide dynamic range (WDS) phenotype
What is the receptive field?
The area in the periphery that when stimulated causes activation of a neuron
What is the role of the receptive field in central sensitisation?
Changes to receptive field facilitates plasticity in nociceptive processing
NS & WDS neurons have significant input from nociceptors in their receptive field
- also have SMALL AMPLITUDE synaptic inputs from low threshold afferents and nociceptor inputs from OUTSIDE their receptive fields, these inputs constitute a SUBLIMINAL FRINGE that does not normally drive output from the cells (i.e. some activity but not enough to cause AP in DH)
If there is central sensitisation, the SUBLIMINAL FRINGE can be RECRUITED so that it does start to drive output from the cells
What evidence is there for receptive field changes in central sensitisation?
Rat foot: measure output from dorsal horn neuron in response to stimulation
A1 on foot = low probability of firing zone
B1 on foot = outside firing zone (no action potentials)
When apply mustard oil to area outside of these areas, change so that both become part of the firing zone
*stimulating these areas = massive action potential generation in dorsal horn neurons (therefore there has been recruitment of subliminal zone, driving output)
What are the underlying mechanisms of central sensitisation?
Activity evoked in dorsal horn neurons by input from C nociceptors
- repeated heat stimuli
- electrical stimulation of C fibres
- chemical activation of C fibres
Noxious stimulus must be intense, repeated & sustained.
Two phases of CS recognised:
- Early: PHOSPHORYLATION dependent / transcription independent (changes in glutamate receptor & ion channel properties)
- Late: TRANSCRIPTION dependent (synthesis of new proteins): longer lasting changes, associated with chronic inflammatory & neuropathic pain
How does early phase of CS occur?
Dorsal horn: host of receptors e.g. AMPARs, neurokinin (SP) receptors, CGRP receptors
Also NMDA receptors (but normally blocked by Mg), in nociceptive state: NMDAR doesn’t participate in depolarisation due to Mg block
C fibre primary afferent activity elicits SLOW synaptic potentials in dorsal horn neurons → TEMPORAL and SPATIAL SUMMATION with activation of different C fibres → prolonged/progressive depolarisation of the dorsal horn membrane → removal of the voltage-dependent Mg²⁺ block
*Glutamate binding to NMDAR → channel opening → Na⁺ entry & most importantly Ca²⁺ entry (inward current & cell depolarisation)
Many mediators and neurotransmitters involved:
- Substance P (SP) and NK1 receptors (if you ablate NK1 positive neurons in spinal cord, leads to reduction in central sensitisation in animal models)
- Metabotropic glutamate receptors
- BDNF
- NO
- Bradykinin
How does calcium influx into dorsal horn neurons occur in CS?
Calcium influx into dorsal horn nociceptive cells
- Via NMDARs
- Via calcium permeable AMPARs
- Via voltage-gated Ca²⁺ channels
- Release from intracellular stores via mGluRs
