Neurophysiology + Pain Flashcards
What is pain?
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
What is wind-up?
Phenomenon when a repeated stimulus (with no change in strength) causes an increase in response from dorsal horn neurons mediated by the release of excitatory neuromediators
What is hyperalgesia?
Increased pain from a stimulus that normally provoke pain.
Two types - primary and secondary
What is allodynia?
Pain due to a stimulus that does not normally provoke pain; e.g light touch or cold breeze may be perceived as pain.
What is a nociceptor?
Free, unmyelinated nerve ending of a primary afferent neuron (1st order), that depolarises in response to stimuli that are associated with cellular damage and transmits the signal to the spinal cord, where it synapses with a secondary afferent neuron (2nd order)
SNS segment level
T1-L3
PNS emerges from?
CN III, VII, IX and X; and S2-4 sacral segments
Neurotransmitter at preganglionic fibre
SNS + PNS - ACh (nicotinic receptor)
Neurotransmitter at postganglionc fibre/ effector organ
SNS - NA (ACh receptor)
PNS - ACh (muscarinic receptor)
Adrenergic receptors
7 transmembrane segments, coupled to GPCR
A1 (postsynaptic) -> Gq -> activates phospholipase C -> IP3 + DAG
=> Vasoconstriction of blood vessels in skin, GIT, kidney, brain
=> Contraction of SM of ureter, urethral sphincter, vas, uterus, ciliary body
=> Glucose metabolism - gluconeogensis, glycolysis
A2 (presynaptic) -> Gi -> ↓adenyl cyclase -> ↓cAMP
=> Sedation, analgesia, ↓SNS, modulate descending pain pathways
=> Glucose - inhibits insulin release, stimulates glucagon release
=> Contraction of anal sphincter
=> Inhibits NA release
B1 (postsynpatic) -> Gs -> ↑adenyl cyclase -> ↑cAMP
=> CVS - ↑HR, ↑conduction, ↑EF
=> ↑renin release by JG cells
=> ↑hunger
B2 (postsynaptic) -> Gs -> ↑adenyl cyclase -> ↑cAMP
=> SM relaxation - bronchus, bronchiole, detrusor, uterine
=> Contraction of urethral sphincter
=> ↑renin release by JG cells
=> Glucose - inhibits insulin release, stimulate gluconeogensis, glycolysis
B3 -> Gs -> ↑adenyl cyclase -> ↑cAMP
=> Lipolysis
D1 -> Gs -> ↑adenyl cyclase -> ↑cAMP
=> CNS - modulate extrapyramidal activity
=> Vasodilator renal vessels
D2 -> Gi -> ↓adenyl cyclase -> ↓cAMP
=> ↓pituitary hormone
=> Inhibit NA release
Nicotinic ACh receptor effects
Ion channels => changes in cell electrical potential
Activate postglanglionic junctions of both SNS + PNS, + found in NMJ
Peripheral NS
- Transmit outgoing signals from presynaptic to postsynaptic cells within SNS and PSNS
- Receptors found on skeletal muscle that receive ACh for muscular contraction -> EPSP by incr Na+ and K+ permeability
Also found in autonomic ganglia and brain
Muscarinic ACh receptor effects
GPCR (similar to adrenergic receptors), 7 transmembrane configuration
M1, 3, 5 - couples to Gq -> stimulation phospholipase -> ↑IP3 -> ↑DAG -> ↑Ca2+ release from stores -> depolarisation/ ↑excitability
M2,4 - Gi -> ↓adenyl cyclase -> ↓cAMP -> ↓protein phosphorylation -> ↓Ca2+ -> presynaptic inhibitory effect
M1 + M4 - brain
M3, M4 - lung, GIT, glandular tissue
M2 - cardiac tissue
Muscarinic effects
- Bradycardia, salivation, bronchoconstriction, mitosis, incr GIT motility
GPCR - M1 to M5
○ (+) → stimulates the organ, Gq coupled receptor (-) → inhibits the organ, Gi coupled receptor
- M1 (+); M2 (-); M3 (+); M4 (-); M5 (+)
- M1, M4, M5 = CNS 🧠.
- M2 = 🫀
- M3 = everywhere else except for gastric acid secretion (← M1 effect blocked by piperizine for PUD)
Cushing’s Triad
Incr ICP, bradycardia and hypertension
Autonomic dysreflexia/ hyperreflexia
Results from chronic disruption of efferent impulses down the spinal cord, i.e in spinal cord trauma or tumour impingement. More common in lesions above T5.
Stimuli, e.g bladder distention, bowel distention or surgical stimulation -> exaggerated sympathetic response due to loss of normal inhibitory impulses from areas above the level of the lesion.
Sweat glands - receptor and stimulation? Blocked by?
Have muscarinic receptors.
Stimulated by ACh.
Blocked by muscarinic antagonists, e.g atropine or peripheral nerve block
Central control of the ANS?
Mediated in the hypothalamus and medulla oblongata
Saltatory conduction
Where AP can leap from node to node, allowing rapid conduction along axons.
Neurons
Excitable cells; receive, process, integrate and transmit signals
Action potential
Transient reversal of the membrane potential that occurs in excitable cells, including neurone, muscle cells and some endocrine cells.
- Is an ‘all or nothing’ event
Refractory Period
Time following an AP when a further AP either cannot be triggered whatever the size of the stimulus (ARP) or only with application of stimulus of increased size (RRP)
Dorsal column/ medial lemniscal pathway
- Touch, vibration and proprioception
- Ascend ipsilaterally in the dorsal columns to the medulla
=> Synapse in gracious and cuneate nucleus
=> First order neurons extremely long - Second order neuron decussate in medulla and ascend in the medial lemniscus to end in the contralateral ventral posterior lateral (VPL) nucleus
- Third order - then travel to primary somatosensory cortex
Ventrolateral spinothalamic tract
- Mediates pain and temperature
- First order neurons - fibres from nociceptors and thermoreceptors synapse on neurons in the dorsal horn of the spinal cord
- Second order - decussate in the anterior comminsure and then ascend in the ventrolateral spinothalamic tract to the thalamic ventral posterior lateral nucleus (VPL)
Third order - then travel to primary somatosensory cortex
Primary afferents for pain
A∂ fibres
- Myelinated
- 2-5um diameter
- Fast conduction 15-20m/s
- Responds to mechanical and thermal stimuli
- Produce rapid, sharp, well localised pain
C-fibre
- Unmyelinated
- <2um diameter
- Slow conduction 0.5m/s
Respond to mechanical, thermal and chemical stimuli
- Produce dull, poorly localised pain follow A∂ response
Modulation of pain signal
3 mechanisms
- Segmental inhibition (gate control theory)
- Descending inhibition (noradrenergic and serotonergic)
- Endogenous opioid system
Segmental inhibition
- Gate control theory
=> Aß fibres are activated by tactile and noxious stimuli
=> Converge on the same secondary afferent neurons in the substantial gelatinosa as C-fibres
=> Aß fibres activate inhibitory in SG -> decr signals transmitted via C-fibres
Descending inhibition
- Periaqueductal grey area of the midbrain
- PAG => RVLM => dorsal horn in spinal cord => decr transmission by secondary afferent spinothalamic neurons via direct action and also action on inhibitory neurons (use GABA and glycine neurotransmitters)
- Main neurotransmitters are serotonin and NA
- Centrally acting a2 agonists (clonidine), SSRIs and TCAs are thought to have their analgesic effect via this pathway
Opioid system
- Opioid receptor and endogenous opioids (enkephalins, endorphins, dynorphin) are found mainly in PAG, ventral medulla and dorsal horn of the spinal cord
- Opioids can modulate pain transmission at two levels
=> Incr descending inhibition
=> Decr transmission by secondary afferents in the dorsal horn
Acute to chronic pain
Chronic pain >3months, initial insult resolved
Primary sensitisation
- Inflammatory response
- Release of mediators, e.g HA, BK, SP, NK-A
- Mast cell degranulation, vasodilation, chemotaxis
- Nerve damage -> incr discharge
Central sensitisation
- Incr NMDA activity
- Windup
- Long term potentiation - persistent change with synaptic reinforcement that occurs through altered gene expression
Neuropathic pain
Pain caused by a lesion or disease of the somatosensory nerve system. May originate from PNS or CNS.
Mechanisms
- Demyelination with exposed axons firing ectopic AP, i.e diabetic neuropathy
- Episodic pain with electric/ burning sensation
- Transected neurons - attempt to regrow the the aid of nerve growth factors. May be disorganised, sprouting nerve endings that may spontaneously generate AP, also increase sensitivity to mechanical stimuli => pain
Prostglandins
Three main actions
- Pain, inflammation, pyrexia
Synthesised
- Via COX pathway
Roles in pain
- Nociception, hyperalgesia, alloodynia (inflamed tissue increased PG production -> incr nociceptor activation and sensitisation)
- Production of PGE2 which sensitises peripheral nerve endings to painful stimuli => peripheral and central sensitisation
- PGE compound inhibit release of NA -> impairs descending inhibition pathway
Role in inflammation
- WBC release cytokines -> production of PGs
- Cause vasodilation and oedema, and leukocyte infiltration
- Contributes to immune suppression
Pyrexia
- PGE2 acts in hypothalamus to increase the temp set point => fever’
Main prostaglandins
- PGI2 - bronchodilation, vasodilation, contracts sphincters in GIT (iloprost is synthetic analogue)
- PGD2 - found in mast cells
- PGE1 (misoprostol is synthetic version, bind all EP receptors except EP1)
- PGE2 (dinoprostone) - vasodilator, GIT contraction
- PGF2-alpha (carboprost)
- TXA2
NMDA Receptors
Structure
- Ligand gated voltage dependent glutamate receptor
- Located in spinal cord + brain
- Transmembrane protein - tetramers with 4 subunits around central ion pore
=> 2x NR1 subunits (pore forming)
=> 1x NR2A subunit (binds glutamate)
=> 1x NR2B (binds glycine)
MoA
- Pore blocked by Mg2+ in resting state
- Priming of NMDA receptor - co-release of glutamate acting on AMPA receptors, partial depolarisation of membrane, removes Mg plug
- Requires coactivation by glycine
- Results in Na and Ca influx into cell => secondary events => early gene induction, production of NO via Ca-calmodulin activation of nNOS, activation of second messengers
Physiological roles
- Central sensitisation - WDR neurone, NMDA activation via priming, incr receptor excitability short term (wind up, hyperalgesia, allodynia), synaptic reinforcement long term (long term potentiation)
- Neuroplasticity
- Excitotoxicity
- Opioid tolerance
NMDA antagonists
- Ketamine, xenon, N2O, methadone (weak), ethanol (weak), tramadol (weak)
Pain in elderly
CNS
- Neuronal atrophy -> reduction in neuronal mass -> cognitive decline and slower reflexes
- Brain compensates
=> Redundancy - more neurons than required for normal cognition
=> Neuroplasticity - more connections formed
=> Neurogensis - certain parts of brain can produce new neurone (hippocampus and basal ganglia)
- Endogenous descending inhibitory pathways (esp opioids) reduced with aging
- Decr CBF
- Overall - altered sensory and emotional perception of pain (overall incr pain tolerance), inability to voice pain, inability to react to pain
PNS
- Neuronal atrophy -> reduction in both myelinated and unmyelinated axons and number of synapses
- Substance P + calcitonin gene relate peptide (2 major neurotransmitters) decreased
- Results in slower transduction and transmission of painful stimuli
ANS
- Ageing -> incr circulating NA but decr response -> decr SNS tone
- Results in decr SNS response (tachycardia and HTN) to painful stimuli
ICP
Normal ICP 5-15mmHg
Determined by
- Cranial volume (fixed)
- Cranial contents (bloods, CSF, parenchyma)
=> Brain volume 85%
=> CSF 10% (150mL)
=> Blood 5% (50-75mL)
Monroe-Kellie Doctrine
Within the cranial vault changes in any one component will alter the volume of one or more of the other components
- Brain tissue (85%), CSF (10%) and blood volume (5%) determine ICP
Increased ICP
CSF displacement
- Displaced from cranium to spinal subarachnoid space
- CSF formation remains constant
- Venting of CSF - reabsorption rate increases
Venous displacement
- Dural venous sinuses compressed displacing venous blood into IJV
Meningeal distention
- Dura bulge out accomodating
IOP
Normal 15mmHg
Similar physiology to ICP
Determinants
- Amount of vitreous humour
- Amount of aqueous humour
- Amount of blood
- Volume of globe
CBF + autoregulation
~750mL/min or 15% of CO or 50ml/100g brain tissue
CBF = CPP/ CVR
CPP = MAP - CVP (ICP)
Autoregulation
- Maintains CBF over range of MAP 50-150mmHg
- Chronic systemic HTN shifts autoregulation curve to right
- Attenuated by hypercapnia, hypoxemia, and volatiles
- Myogenic - Bayliss effect (response to incr/decr wall tension) - incr flow -> incr stretch -> reflex contraction -> decr rad -> decr flow
- Metabolic - decr CMR -> decr H/K/ adenosine/ lactate/pCO2 + incr pO2 -> vasoconstriction -> decr radius -> decr flow
Physiological
- decr O2 <50mmHg -> vasodilator -> incr rad -> incr CBF (non linear)
- incr PaCO2 -> vasodilator (linear 20-80mmHg) -> Incr CBF
- decr temp -> decrease CMR -> decr CBF via metabolic autoregulation (near linear)
EEG
EEG is the summation of excitatory and inhibitory potentials of the cortical pyramidal cells. EEG is typically small with low voltage in the order of 0-200 μV. The EEG is characterized by its frequency and amplitude of the waveform.
4 main types of wave - alpha, B, theta, delta
Gamma 30-80Hz
Beta 14-30Hz
Alpha 8-12Hz
Theta 4-8Hz
Delta 0-4Hz
Normal EEG in an awake individual is asynchronous, of low voltage and high frequency
CSF
150mL
Daily production ~500ml/day, 0.3ml/min
Roles
- Protection + buoyancy, decr effective weight
- Buffer changes in ICP
- Medium for acid/base sensing + regulation
- Maintain stable ionic environment
- Nutrient + waste removal
- Return of interstitial protein to circulation
Production
- 2/3 by choroid plexus
- 1/3 by ependymal cells
- Rate of CSF production constant, affected by CBF/ CPP, if CPP <70mmHg decr CSF formation due to decr cerebral + choroid plexus blood flow (not affected by ICP)
Reabsorption
- Increases linearly with incr ICP up to 22.5mmHg. <7mmHg no reabsorption
CSF vs plasma
- CSF Cl- + Mg2+ higher than plasma
- Everything else + pH is lower than plasma
Hypothalamus
Functions
- Temperature
- Water balance
- Behaviour/ emotion
- Appetite
- Control of ant. pituitary gland hormones by secretions of NTs
- Production of post. pituitary gland hormones
- Autonomic
Structure
- Anterior
- Posterior
- Medial
- Lateral
Water
- Paraventricular region
- Thirst centre activated by incr tonicity, hypovolaemia, dry mouth
- Incr ADH synthesis
- Incr thirst
Endocrine
- Post - Releases into infundibulum from supraoptic and paraventricular nuclei
- ADH
- Oxytocin
Ant - secretes into hypophyseal portal syste
- CRH
- TRH
- GHRH
- GnRH
Autonomic
- Anterior - depressor area (control of PSNS)
- Post - SNS response via RVLM + interomedial lat horn
Food
- Ventromedial - senses [glucose], induces satiety
- Lateral - induces hunger and food seeking
Sleep-wake
- Suprachiasmatic nucleus - generated Cricardian rhythm (input from photosensitive cells)
Emotion
- Connected to other limbic structures
- Mediates emotional expression via autonomic and osmotic nervous systems
- Defence area (fight or flight) - anterior perifornical region, activated by limbic system
- Depressor area - anterior region
Sexual function
- Control of pituitary hormone - puberty, menstrual cycle
- Medial region control sexual behaviour
