Case 2 Flashcards
describe the organisation of the spinal cord
- the arrangement of paired dorsal and ventral roots is repeated 31 times down the length of the spinal cord
- each spinal nerve, consisting of a dorsal root and ventral root axons, passes through a notch between the vertebrae - intervertebral foramen
- the 31 spinal segments are divided into 5 groups:
- cervical C1 - C8
- thoracic T1 - T12
- lumbar L1 - L5
- sacral S1 - S5
- coccygeal Cy1
what is a dermatome?
the area of skin innervated by the right and left dorsal roots of a single spinal segment, thus there is one-to-one correspondence between dermatomes and spinal segments
how do dermatomal maps vary?
among individuals
do the dermatomes overlap? why?
they overlap substantially, so that injury to an individual dorsal root does not lead to complete loss of sensation in the relevant skin region
what happens when a dorsal root is cut? what would have to happen to lose all sensation?
- when a dorsal root is cut, the corresponding dermatome on that side of the body does not lose all sensation
- the residual somatic sensation is explained by the fact that the adjacent dorsal roots innervate overlapping areas
- to lose all sensation in one dermatome, therefore, three adjacent dorsal roots must be cut
what is the overlap more extensive for? what does this mean?
touch, pressure, and vibration than for pain and temperature
thus, testing for pain sensation provides a more precise assessment of a segmental nerve injury than does testing for responses to touch, pressure, or vibration
what does the segmental distribution of proprioceptors follow and not follow?
it does not follow the dermatomal map but is more closely allied with the pattern of muscle innervation
what is knowledge of dermatomes essential for?
the clinical neurological evaluation of patients, particularly in determining the level of a spinal lesion
what are the white matter tracts often called?
columns
what is each half of the spinal grey matter divided into?
- dorsal horn
- intermediate zone (lateral horn)
- ventral horn
what are neurones that receive sensory input from primary afferents called? where do most of them lie?
- second-order sensory neurones
- most of the second-order sensory neurones of the spinal cord lie within the dorsal horns
what are two main functions of the spinal cord?
- to specify the characteristics of a stimulus in terms of its modality and position - function of grey matter
- to serve as a relay system for impulse propagation to and from the brain - sensorimotor information is relayed via the dorsal, lateral and ventral funiculi of the white matter
what are the two types of spinal cord cells?
- interneurones
- 97% of cells in spinal cord
- involved in modulating sensory input and motor output and make local connections with other cells in the spinal cord - projection neurones
- 3% of cells in spinal cord
- subdivded into:
- cells that give rise to axons of the ascending pathways, comprising of 1% population
- motor neurones, representing the remianing 2%, whose axons project from spinal cord to innervate skeletal muscles
how can spinal cord interneurones be further classified?
- inhibitory neurones
- these limit the RF (receptive field - area of skin where a stimulus can excite the sensory fibre) size or activity of other neurones
- these use inhibitory neurotransmitters such as Y-aminobutyric acid (GABA), glycine and enkephalin to regulate the activity of other neurones - excitatory neurones
- these cells use glutamate and various neuropeptides as neurotransmitters
- their stimulation evokes action potentials in other cells
describe the origination of the somatic sensation
- somatic sensation originates from the activity of afferent nerve fibres whose peripheral processes branch within the skin or in muscle
- the cell bodies of afferent fibres reside in a series of ganglia that lie alongside the spinal cord and brainstem and are considered art of the peripheral nervous system
- neurones in the dorsal root ganglia and in the cranial nerve ganglia are the critical links supplying the central nervous system circuits with information about sensory events that occur
- action potentials generated in afferent fibres propagate along the fibre and past the location of the cell body in the ganglia until they reach fibres’ synaptic terminals, which are located in various target structures of the central nervous system
- peripheral and central components of afferent fibres are continuous, attached to the cell body in the ganglia by a single process - for this reason, neurones in the dorsal root ganglia are often called pseudounipolar
what happens when afferent fibres do and don’t have receptors?
- they are often capsulated by specialised receptor cells (mechanoreceptors) that help tune the afferent fibre to particular features of somatic stimulation
- afferent fibres that lack specialised receptor potentials are referred to as free nerve endings and are especially important in the sensation of pain
what is sensory transduction?
process in which energy of a stimulus is converted into an electrical signal in the sensory neurone
what are the different types of afferent nerve fibres?
Ia/A-alpha fibres:
- largest diameter (13-20um)
- myelinated
- supply sensory receptors in muscles
- responsible for proprioception
A-beta fibres:
- smaller diameter than A-alpha (6-12um)
- myelinated
- most information for touch (light touch, deep touch), proprioception, heavy pressure, vibration, skin stretch
A-delta fibres:
- smaller diameter than A-beta (1-5um)
- myelinated
- information about pain (nociceptors) and temperature (thermoreceptors)
C fibres:
- smaller diameter than A-delta (0.2-1.5um)
- non-myelinated
- information about pain and temperature
how does diameter relate to speed of conduction? why is this useful?
- the largest, swiftest axons (A-alpha) are used to carry sensory information about the most rapidly changing stimuli over the longest distances (e.g., stretch receptors in muscle, mechanoreceptors in tendons and skin), or they are used to control finely coordinated contractions of muscles
- the thinnest, slowest C fibres are mainly sensory axons related to chronic pain and temperature, for which the speed of the message is not as critical
where do the different afferent fibres project into the dorsal horn?
A-beta fibres project mostly to the deep layers of the posterior horn, where as A-beta and C fibres project mostly to the superficial layers
what are rapidly and slowly adapting afferents? when are each useful?
some afferents fire rapidly when a stimulus is first presented, then fall silent in the presence of sustained stimulation; others generate a sustained discharge
- rapidly adapting afferents are thought to be particularly effective in conveying information about changes in ongoing stimulation such as those produced by stimulus movement
- slowly adapting afferents are better suited to provide information about the spatial attributes of the stimulus, such as size and shape
what is the threshold like for mechanoreceptors?
low-threshold
even weak mechanical stimuli of the skin induces them to produce an action potential
what type of afferent fibre are all low-threshold mechanoreceptors innervated by?
A-beta (relatively large myelinated axons), ensuring the rapid central transmission of tactile information
what are the different types of mechanoreceptors?
- Merkel’s disks
= highest spatial resolution, allows them to resolve tiny spatial details - ideal for processing information about form and texture - Meisenner corpuscle
= account for 40% of hand mechanosensory information - efficient in processing information about low-frequency vibration that occurs when objects move across the skin - Ruffini endings
= essential to internally generated stimuli (e.g. finger movements) - Pacinian corpuscle
= detecting vibrations transmitted through objects that contact the hand
What are the sensory modalities of the follow receptors?
- muscle spindle
- golgi tendon organ
- Meissner corpuscle
- Merkel’s disks
- Pacinian corpuscle
- Ruffini endings
- nociceptors (free nerve endings)
- thermoreceptors
- proprioception
- proprioception
- heavy pressure
- light touch (discriminative touch)
- deep touch / vibration
- deep touch / vibration / skin stretch
- pain
- temperature
muscle spindles
- what are they?
- where found?
- what consist of?
- density of spindles in muscles?
- mechanoreceptors specialised for proprioception
- found in skeletal muscles
- consist of 4-8 specialised intrafusal muscle fibres surrounded by a capsule of connective tissue
- the intrafusal fibres are distributed among the extrafusal fbres of skeletal muscle in a parallel arrangement
- in the largest of the intrafusal fibres, the nuclei are collected in an expanded region named the nuclear bag fibres
- the nuclei in the remaining 2-6 smaller intrafusal fibres are lined up single file, with the result that these fibres are called nuclear chain fibres
- the intrafusal muscle fibres contract when commanded to do so by motor axons derived from a pool of specialised motor neurones in the spinal cord (y motor neurones)
- the major function of muscle spindles is to provide information about muscle length (that is, the degree to which they are being stretched)
• The density of spindles in human muscles varies. Large muscles that generate coarse movements have relatively few spindles; in contrast, extraocular muscles and the intrinsic muscles of the hand and neck are richly supplied with spindles
what are golgi tendon organs?
- distributed among the collagen fibres that form the tendons
- these inform the CNS about changes in muscle tension
where are the ascending pathways located?
in specific areas of the white matter of the spinal cord
describe the concepts of a somatosensory pathway
- a ‘first order neurone’ comes ipsilaterally from a receptor in the periphery and goes into the spinal cord or medulla
- nerve cell body is found in a ganglion that lies alongside (outside) the spinal cord and brainstem and is considered part of the PNS
- the 1o neurone synapses with a 2o neurone in the spinal cord or medulla
- the 2o neurone decussates and ascends up the spinal cord to the thalamus in the brain
- the thalamus is the main sensory relay centre
- in the thalamus, the 2o neurone synapses with a 3o neurone which then goes to the relevant sensory cortex
- the cell body of the 3o neurones are found in the ventral posterior nucleus in the thalamus
what are the ascending tracts we need to know?
- spinothalamic tracts - lateral and ventral
2. dorsal columns - fasiculus gracilis and fasciculus cuneatus
what does the spinothalamic tract transfer information about?
pain, temperature, non-discriminative touch, and pressure
describe the route of the spinothalamic tract
- 1o neurone comes from the peripheral receptors (for pain, temperature, non-discriminative touch, and pressure) and terminate in the spinal cord
- the nerve cell body is found in the dorsal root ganglia
- here, the 1o neurone synapses with a 2o neurone
- the 2o neurone leaves the dorsal horn and crosses the white matter commissure to reach the spinothalamic tract, where it ascends to the contralateral thalamus
- pain & temperature = lateral spinothalamic tract
- crude touch & pressure = ventral spinothalamic tract
- the 3o neurone then goes to the relevant sensory cortex
what does the dorsal columns transfer information about?
- this tract takes information about: discriminative touch, vibration and proprioception
describe the route of the dorsal columns
- the 1o neurone comes from the peripheral receptors (for discriminative touch, vibration and proprioception) and enters the fasiculus gracilis/cuneatus of the spinal cord and immediately ascends ipsilaterally to the medulla (nucleus gracilis/cuneatus)
- fasiculus gracilis brings sensory infromation from the mid-thoracic and lower limbs (‘g’ for ground) - more medial of two dorsal columns
- fasiculus cuneatus brings sensory information from upper limbs
- the nerve cell body is found in the dorsal root ganglia
- in the medulla, the 1o neurone synapses with a 2o neurone in the nucleus gracilis/cuneatus
- the axons of the 2o neurone exiting the dorsal column nuclei are called the internal arcuate fibres - these decussate int he medulla and form the medial lemniscus
- the medial lemniscal fibres ascend to the somatic sensory portion of the thalamus
- in the cross-section through the medulla, the medial lemniscal axons carrying information from the the lower limbs are located ventrally, whereas the axons related to the upper limbs are located dorsally
- as the medial lemniscus ascends through the pons and midbrain, it rotates 90* laterally, so the fibres representing the upper body are eventually located int he medial portion of the tract and those representing the lower body are eventually located in the lateral portion
- the medial lemniscus synapses in the ventral posterior lateral nucleus (VPL) of the thalamus
- 3o neurones in the VPL send their axons via the posterior limb of the internal capsule to terminate in the postcentral gyrus (primary somatosensory cortex)
- neurones in the VPL also send axons to the secondary somatosensory cortex (S2) (a region that lies in the upper bank of the lateral sulcus)
what is the trigeminothalamic system?
• The trigeminal brainstem complex has two major components:
The principal nucleus - responsible for processing mechanosensory stimuli
The spinal nucleus - responsible for processing painful and thermal stimuli
• Thus axons carrying information from low-threshold cutaneous mechanoreceptors in the face terminate in the principal nucleus.
• The second order neurons of the trigeminal brainstem nuclei give off axons that cross the midline and ascend to the VPM nucleus of the thalamus by way of the trigeminal lemniscus.
what does the ventral posterior complex of the thalamus comprise of? and what is it?
- it’s the main target of the ascending somatic pathways
- a lateral and medial nucleus:
- the more laterally located VPL nucleus receives projections from the medial lemniscus carrying all somatosensory information from the body and posterior head
- the more medially located ventral posterior medial (VPM) nucleus receives axons from the trigeminal lemniscus
describe higher-order cortical representations
- somatic sensory information is distributed from the primary somatic sensory cortex to ‘higher-order’ cortical fields (as well as subcortical structures)
- one of these higher-order cortical centers, the secondary somatosensory, receives convergent projections from the primary somatic sensory cortex and sends projections in turn to limbic structures, such as the amygdala and hippocampus
- this latter pathway is believed to play an important role in tactile learning and memory
what is a fundamental feature of the somatic sensory system?
the presence of massive descending projections
- these pathways originate in sensory cortical fields and run to the thalamus, brainstem, and spinal cord
how does the primary somatosensory cortex demonstrate plasticity? and what does this mean?
- this refers to persistent modifications in the structure or functioning of the primary somatosensory cortex
- these modifications are proposed to underlie learning and memory of tactile information, as well as recovery of function after injury
what are the concepts of a somatic motor pathway?
- consists of a upper motor neurone and a lower motor neurone
- the upper motor neurone arises in the primary motor cortex (where its nerve cell body is found) and descends into the brainstem/spinal cord
- in the brainstem/spinal cord, the upper motor neurone decussates and terminates by synapsing with the lower motor neurone in the spinal cord
what are descending pathways/tracts? which ones do we need to know about?
- these tracts carry motor information from the brain to the spinal cord and then to the periphery
- the descending tract we need to know is the corticospinal tract - lateral and ventral
what corticospinal tracts do we have?
lateral and ventral
describe the route of the corticospinal tracts
- the upper motor neurone arises in the motor cortex
- the axon of the upper motor neurone runs through the internal capsule and reaches the medullary pyramids
- here, 75-85% of the axons will decussate and descend down the lateral corticospinal tract
- the remaining 15-25% of the axons will continue ipsilaterally, descending down the ventral corticospinal tract - these will decussate in the spinal cord at the level that they need to exit the spinal cord
what do all upper motor neurones do before they synapse with a lower motor neurone?
decussate
what are the cranial nerves? are they sensory, motor or both?
olfactory I - sensory optic II - sensory oculomotor III - motor trochlear IV - motor trigeminal V - both abducens VI - motor facial VII - motor vestibulocochlear VIII - sensory glossopharyngeal IX - both vagus X - both accessory XI - motor hypoglossal XII - motor
which are the cranial nerves that are both sensory and motor?
trigeminal, glossopharyngeal, and vagus
what cranial nerve cell nuclei?
- these are the nerve cell bodies of the cranial nerves
- these are located in the brainstem
- the motor cell nuclei are the cell bodies of the lower motor neurones
what are cranial nerves?
nerves that originate directly from the brain, in contrast to spinal nerve which emerge from segments of the spinal cord
describe the sensory pathway (for cranial nerves)?
- A ‘first order (1o) neurone’ that comes ipsilaterally from a receptor in the periphery and goes into the spinal cord or the medulla.
- The nerve cell body of the 1o neurone is found in a sensory ganglion in the head region.
- The 1o neurone synapses with a 2o neurone in the brainstem.
- The cell bodies of the 2o neurones are found in the trigeminal sensory nucleus of the brainstem
- The 2o neurone decussates and ascends up the spinal cord to the thalamus in the brain.
- The thalamus is the main sensory relay centre.
- In the thalamus, the 2o neurone synapses with a 3o neurone which then goes to the relevant sensory cortex.
- The cell body of the 3o neurones are found in the ventral posterior nucleus in the thalamus.
GENERAL SENSORY PATHWAYS OF CRANIAL NERVES
1st order – NCB (nerve cell body) in periphery
- Trigeminal ganglion – CN V
- Geniculate ganglion – CN VII
- Superior & inferior ganglia – CN IX & X
2nd order – ALL (?) NCB in trigeminal sensory nucleus of brainstem, fibres decussate
3rd order – NCB in VP thalamus, axons project to primary sensory cortex
how many cranial nerves (1o neurones) that bring general sensation? and what are they? and where are their cell bodies found?
4
Their cell bodies are found in specific ganglia:
- trigeminal - trigeminal ganglion
- facial - geniculate nucleus (thalamus)
- glossopharyngeal - superior and inferior ganglia
- vagus - superior and inferior ganglia
where do all 2o neurones, regardless of where the sensory information is coming from, synapse at?
at the trigeminal sensory nucleus
what does the trigeminal sensory nucleus consist of?
3 subnuclei:
- chief sensory nucleus - touch and pressure
- spinal nucleus - pain and temperature
- mesencephalic - proprioception
(not to be confused with the trigeminal ganglion, which is just for the trigeminal nerve)
what is a ganglion? what is a nucleus?
a ganglion is a cluster of nerve cell bodies outside the CNS
a nucleus is a cluster of nerve cell bodies in the CNS
what is the corticobulbar tract for? describe it.
motor information
- the upper motor neurone axons arise at the cortex and descend to the brainstem (bulb)
- here, the upper mtoor neurone decussates and then synapses with the lower motor neurone
- the lower motor neurone then exits the spinal canal and travels to its target
what is a difference between the corticobulbar tract and corticospinal tract?
with the corticobulbar tract, some lower motor neurones are bilaterally innervated (i.e. two upper motor neurones - one from the right/left side of head - synapse with it in the brainstem)
what is the only (motor/both) cranial nerve to not receive bilateral innervation? what does it receive instead?
hypoglossal nerve - it receives contralateral innervation
which cranial nerves receive bilateral innervation?
Oculomotor (III) Trochlear (IV) Trigeminal (V) Abducens (VI) Glossopharyngeal (IX) Vagus (X) Accessory (XI) - (facial)
why are bilaterally innervated cranial nerves an advantage?
- because if there is an upper motor neurone (UMN) lesion which damages the UMN, then they still have a second form of innervation as a compensation
- for the hypoglossal nerve, the UMN will cause dysfunctin of the nerve
what innervation does the facial nerve have?
parasympathetic as well as somatic
where does the facial nerve supply motor information?
to all the facial muscles
describe the facial motor nucleus
- different parts
- how each is innervated
- made up of two parts
- the nerve cell bodies in the upper part supply muscles of the face above the eye level
- the nerve cell bodies in the lower part supply the muscles below the eye level
- the upper part of nucleus is bilaterally innervated
- the lower part of nucleus is contralaterally innervated
where does each cranial nerve supply motor or sensory innervation?
olfactory:
- sensory = nose
optic:
- sensory = eye
oculomotor:
- motor = all eye muscles except those supplied by IV and VI
trochlear:
- motor = superior oblique muscle
trigeminal:
- sensory = face, sinuses, teeth, etc.
- motor = muscles of mastication
abducent:
- motor = lateral rectus muscle
facial:
- motor = muscles of the face
vestibulocochlear:
- sensory: inner ear
glossopharyngeal:
- motor = pharyngeal musculature
- sensory = posterior part of tongue, tonsil, pharynx
vagus:
- motor = heart, lungs, bronchi, gastrointestinal tract
- sensory = heart, lungs, bronchi, trachea, larynx, pharynx, gastrointestinal tract, external ear
accessory:
- motor = sternocleidomastoid and trapezius muscles
hypoglossal:
- muscles of the tongue
describe the general autonomic motor pathway and what happens for sympathetic and parasympathetic
- this starts in the hypothalamus
- the UMN descends to the spinal cord
- there are two LMNs: a pre-ganglionic neurone and a post-ganglionic neurone
- in the spinal cord, the UMN synapses with the pre-ganglionic neurone
- the pre-ganglionic neurone leaves the spinal canal and synapses with the post-ganglionic neurone in a ganglion
- the post-ganglionic neurone travels to its target
parasympathetic:
- the ganglia are near to the target itself
- this means that the pre-ganglonic neurone has a long axons
sympathetic:
- the ganglia are close to the spinal cord
- this means that the pre-ganglionic neurone has a small axon
which cranial nerves have parasympathetic innervation?
oculomotor, facial, glossopharyngeal, and vagus
what is the sympathetic chain? what does it contain?
- lies on either side of the vertebral column
- contains the ganglia where the pre-ganglionic and post-ganglionic neurones of the sympathetic nervous system synapse (they have a short axon)
what are the different routes to take in the sympathetic chain?
- synapses in paravertebral ganglion at own spinal level
- passes up/down the chain to synapse in cervical or pelvic paravertebral ganglion
- passes straight through chain to synapse in prevertebral ganglion (symapthetic ganglia that lies between teh paravertebral and the target organ)
- synapses in the paravertebral ganglion
- the postganglionic neurone enters the grey ramus communicates and returns to the ventral ramus in order to pass to the periphery
- travels up the chain to synapse in a paravertebral ganglion in the neck or down the chain to synapse in a paravertebral ganglion in the pelvis
- the postganglionic neurone enters the grey ramus communicates at the new level
- it passes to the periphery via the adjacent ventral ramus
- passes straight through the chain to synapse in a prevertebral ganglion (e.g. superior mesenteric ganglion)
- the preganglionic neurone is termed a splanchnic nerve
- the postganglionic neruone passes directly to the effector organ
what are the pathways for body proprioceptive information?
- 10 proprioceptive afferents that enter the spinal cord between T1-L2 synapse on neurons in Clark’s nucleus, a nucleus in the medial aspect of the dorsal horn.
- 20 neurons in Clark’s nucleus send their axons into the ipsilateral dorsal spinocerebellar tract where they travel up to the level of the medulla.
- These axons continue into the cerebellum via the inferior cerebellar peduncle, but in their course, give collaterals that synapse with neurons lying just outside the nucleus gracilus.
- Axons of these 30 neurons decussate and join the medial lemniscus accompanying it to the VPL of the thalamus.
- The spinocerebellar pathway consists of a sequence of only two neurons.
- Axons enter below L2 ascend through the dorsal column and then synapse with neurons in Clark’s nucleus and constitute the ventral spinocerebellar pathway.
- These fibres decussate, ascend on the contralateral side of the cord and decussate again to enter the cerebellum via the superior cerebellar peduncle.
- 10 proprioceptive afferents from the upper limbs enter the spinal cord and travel via the dorsal columns (fasciculus cuneatus) up to the level of the medulla where they synapse on proprioceptive neurons in the nucleus cuneatus.
- 20 neurons send their axons across the midline, where they join the medial lemniscus and ascend to the VPL of the thalamus.
what is the pathway for facial proprioceptive information?
- Proprioceptive information from the face is conveyed through the trigeminal nerve.
- The cell bodies of the 10 proprioceptive neurons for the face are found in the mesencephalic trigeminal nucleus.
- Information from the proprioceptive afferents also reaches the thalamus and is represented in the somatic sensory cortex.
what is the nociceptive system?
a specific system of high-threshold peripheral and central neurones designed to respond only to noxious stimuli (produced when potentially or actually damaging)
why is nociceptive pain essential?
it’s an essential early warning device that helps protect us from the dangerous environment we find ourselves in
what are the different types of nociceptor afferents?
- either A-delta myelinated axons or C fibre unmyelinated axons
- even though the conduction of all nociceptive information is relatively slow, there are fast (A-delta) and slow (C) pain pathways
what are nociceptors? where are cell bodies located?
free nerve endings, whose cell bodies are located in the spinal ganglia (dorsal root ganglia) for the body and the trigeminal ganglia of the face
nociceptors
- when are they activated
- how do they respond
- what does activation result in
- They are only activated when the stimulus reaches a noxious threshold.
- They respond progressively, according to the intensity of the stimulus.
- Activation of nociceptors results in the opening of cation channels (mainly Na+), which will result in membrane depolarization and the generation of action potentials.
what can continued stimulation of nociceptors do?
can decrease the threshold at which nociceptors respond = sensitisation
what are the major classes of nociceptors in the skin? what do they each respond to?
- A-delta mechanical nociceptors
- A-delta thermal nociceptors
- polymodal nociceptors
- the faster-conducting A-delta nociceptors respond either to dangerously intense mechanical or to thermal stimuli
- other unmyelinated nociceptors tend to respond to thermal, mechanical, and chemical stimuli, and are therefore said to be polymodal - these are associated with C fibres
what is the neurotransmitter for pain afferents?
glutamate
- the release of glutamate from sensory terminals evokes fast synaptic potentials in dorsal horn neurones by activating the AMPA-type glutamate receptors
what is also required for the mediation of synaptic transmission for moderate to intense pain?
substance P
contained within storage granules in the axon terminals and can be released by high-frequency trains of action potentials (in C fibres)
what are the two categories of pain perception?
- a sharp first pain caused by stimulation of the A-delta fibres
- a more delayed, diffuse, and longer-lasting sensation that is called second pain
- this occurs when the stimulus intensity is increased, so that the small-diameter, slowly conducting C fibre axons are brought into play
how is information about pain (as well as temperature) in the body conveyed from the spinal cord to the brain? where first synapse?
through the spinothalamic pathway
- the afferent fibres make their first synapses immediately in the grey matter of the spinal cord mainly in lamina I & V
describe the spinomesencephalic tract
- This tract projects to the midbrain periaqueductal grey (PAG) matter and the superior collicului.
- The PAG has reciprocal connections with the limbic system and receives input from the cortex and hypothalamus.
- Projections to the superior colliculus are thought to influence our eye movements and direct our gaze to the site of injury.
describe the spinoreticular tract
- This tract terminates on the medullary–pontine reticular formation, which in turn projects to the intralaminar thalamic nuclei.
- Unlike the VPL, which projects specifically in a somatotopic fashion to the primary sensory cortex, the intralaminar nuclei project diffusely to the entire cerebral cortex and are thought to be involved in behavioral arousal.
- These projections probably participate together with the spinoreticular tract in a phylogenetically older pain pathway responsible for conveying the emotional and arousal aspects of pain and the transmission of slow pain.
- In addition to pain and temperature, the anterolateral pathways can convey some crude touch sensation. Therefore, touch sensation is not lost when the posterior columns are damaged.
describe the trigeminal pain pathway
• 10 axons carry information from facial nociceptors and thermoreceptors into the brainstem.
• The cell bodies are located in the trigeminal ganglion.
• The central fibres from the trigeminal nerve terminate in the trigeminal sensory nucleus where they synapse with 20 neurons.
• The trigeminal sensory nucleus extends throughout the brainstem and is subdivided into three subnuclei: chief, mesencephalic and spinal nuclei.
• The 10 pain neurons terminate in the spinal trigeminal nucleus, where they synapse with 20 neurons.
• The 20 neurons ascend to the VPM nucleus in the thalamus, via the trigeminothalamic tract.
Information from the body (Spinothalamic) terminates in the VPL nucleus.
Information from the face (trigeminothalamic) terminates in the VPM nucleus.
• These nuclei send their axons to primary and secondary somatosensory cortex.
what are the two forms of pain hypersensitivity?
- thresholds are lowered so that stimuli that would normally not produce pain now begin to (allodynia)
- responsiveness is increased, so that noxious stimuli produce an exaggerated and prolonged pain (hyperalgesia)
(an abnormal state of increased sensitivity to painful stimuli)
what normally happens with sensitisation? what can happen?
- as injured tissue heals, the sensitisation induced by peripheral and central mechanisms typically declines and the threshold for pain returns to preinjury levels
- however, when the afferent fibres or central pathways themselves are damaged (central sensitisation), these processes can persist
- the resulting condition is referred to as neuropathic pain, a chronic, intensely painful experience that is difficult to treat with conventional analgesic medications
describe and explain peripheral sensitisation. why is it important?
- this is a reduction in threshold and an increase in responsiveness of the peripheral ends of the nociceptors (high-threshold pain receptors)
- this results from the interaction of nociceptors with the inflammatory chemicals at the site of tissue damage of inflammation
- the complex chemical signalling that occurs due to this interaction has two effects:
1. protect the injured area - this occurs as a result of painful perceptions produced by ordinary stimuli close to the site of damage
2. promote healing and guard against infection - this occurs by means of local efforts such as increased blood flow and the migration of white blood cells to the site
what is central sensitisation? what causes it?
- this is an increase in the excitability of neurones within the CNS, so that normal inputs begin to produce abnormal responses
- the increased excitability is typically triggered by a burst of activity in nociceptors, which alter the strength of synaptic connections between the nociceptor and the neurones of the spinal cord (activity-dependent synaptic plasticity)
- low-threshold sensory fibres (e.g. for very light touch), begin to activate neurones in the spinal cord (for inputs from the body) or in the brainstem (for inputs from the head) that normally only respond to noxious stimuli - as a rsult, an input that would normally evoke an innocuous sensation now produces pain
- although the pain feels as if it originates in the periphery, it is actually a manifestation of abnormal sensory processing within the CNS
- a transcription-dependent phase of central sensitisation is mediated by increased levels of protein production
- the net effect of these changes is that normally subliminal inputs begin to activate the neurones and pain sensibility is drastically altered
- one of these proteins Cox-2, the enzyme that produces prostaglandin E2
what sensitisation are prostaglandins involved in?
both peripheral and central sensitisation
what does nociceptive pain result from? what does neuropathic pain result from?
- nociceptive pain results from direct activation of nociceptors
- neuropathic pain results from direct injury to nerves
how does inflammation cause pain?
• When tissue is damaged, it results in the process of inflammation.
• The products of tissue damage interact with nociceptors and augment their response.
• These products of tissue damage substances are:
ATP:
This directly depolarises nociceptors.
Bradykinin:
This directly depolarises nociceptors.
In addition, bradykinin stimulates long-lasting intracellular changes that make heat-activated ion channels more sensitive.
Prostaglandins:
These are generated by the enzymatic breakdown of lipid membrane of cells.
Although they do not elicit overt pain, they do increase greatly the sensitivity of nociceptors to other stimuli.
Aspirin and other NSAIDs are useful treatment for hyperalgesia because they inhibit the enzymes (Cox-2) for prostaglandin synthesis.
Substance P:
This is a peptide synthesised by nociceptors themselves.
Activation of one branch of the nociceptor axon can lead to the secretion of substance P by the other branches of that axon in the neighbouring skin.
Substance P causes vasodilation and the release of histamine from mast cells.
Sensitisation of other nociceptors around the site of injury by substance P is one cause of secondary hyperalgesia
what is tactile allodynia?
- pain in response to light brushing of the skin
- caused by central sensitisation
what is primary and secondary hyperalgesia?
primary = this is increased sensitivity to pain within the area of damaged tissue secondary = this is increased sensitivity to pain in the tissues surrounding a damaged area - one cause is due to sensitisation of nociceptors in the surrounding tissue by substance P
what are treatments for hyperalgesia? why do they work?
aspirin and other NSAIDs
- they inhibit the enzymes (Cox-2) for prostaglandin synthesis
what is the gate control theory?
it states that the spinal cord may either block pain signals or allow them to pass onto the brain
- the gate signals are blocked when the ‘gate is closed’
- pain signals pass from the spinal cord to the brain when the ‘gate is open’
- according to the gate control theory, we can be distracted from the pain by release of endorphins (neurotransmitters)
our spinal cord has large (A-beta) and small (C) nerve fibres
- AB fibres close the pain gate
- C fibres activate and open the pain gate
- A balance of spinal input by large AB and small C fibres
- Can get pain relief by increasing Abeta (low threshold for touch) input – ‘shutting the gate’ – activating inhibitory neurones
what can close the pain gate?
massage, acupuncture or electronical stimulation (TENS) - these all create activity in the AB fibres and so close the pain gate
where does herniation of the nucleus pulposus normally extend?
posterolaterally, where the anulus fibrosus is relatively thin and does not receive support from either the posterior or the anterior longitudinal ligaments
which type of herniated IV disc is more likely to be symptomatic? why?
a posterolateral one due to the proximity of the spinal nerve roots
where are posterolateral herniations of the nucleus pulposus most common?
in the lumbar and lumbosacral regions, because the IV discs are largest here and so movements are consequently greater
where do approximately 95% of lumbar disc protrusions occur?
at the L4-L5 or L5-S1 levels
what does the localised back pain of a herniated disc, which is usually acute pain, result from?
- from pressure on the longitudinal ligaments and periphery of the anulus fibrosus
- and from local inflammation caused by chemical irritation by substances from the ruptured nucleus pulposus
what is chronic pain by a herniated disc caused by? how’s it felt?
- results from compression of the spinal nerve roots by the herniated disc
- it’s usually referred pain, percieved as coming from the area (dermatome) supplied by that nerve
how would a prolapsed disc be seen on a radiograph?
- usually seen as decreased intervertebral disc space
- the marked decrease in the radiographic intervertebral space that may occur as a result of acute herniation of a nucleus may also result in narrowing of the IV foramina, perhaps exacerbating the compression of the spinal nerve roots, especially if hypertrophy of the surrounding bone has also occurred
what is sciatica? what is it often caused by? what exacerbates sciatic pain?
- pain in the lower back and hip radiating down the back of the thigh into the leg
- often caused by a herniated lumbar IV disc that compresses and compromises the L5 or S1 component of the sciatic nerve
- the IV foramina in the lumbar region decrease in size and the lumbar nerves increase in size, which may explain why sciatica is so common
- any maneuver that stretches the sciatic nerve, such as flexing the thigh with the knee extended (straight leg raising test), may produce or exacerbate sciatic pain
what’s the general rule about which nerve root is compressed when an IV disc protrudes?
a protruding IV disc usually compresses the nerve root numbered one inferior to the herniated disc; for example, the L5 nerve is compressed by an L4-L5 IV disc herniation
what is lumbar spondylosis?
- term given to the occurrence of degenerate disc disease and osteoarthritic change in the lumbar spine
what is acute lumbar disc herniation often precipitated by? what happens?
trauma, usually by lifting heavy weights while the spine is flexed
the nucleus propulsus may bulge or rupture through the annulus fibrosus, giving rise to pressure on nerve endings in the spinal ligaments, changes in the vertebral joints or pressure on nerve roots
what’s the pathophysiology of lumbar spondylosis?
- The altered mechanics of the lumbar spine result in loss of lumbar lordosis and there may be spasm of the paraspinal musculature.
- Root pressure is suggested by limitation of flexion of the hip on the affected side if the straight leg is raised (Lasègue’s sign).
- If the third or fourth lumbar roots are involved, Lasègue’s sign may be negative, but pain in the back may be induced by hyperextension of the hip (femoral nerve stretch test).
- The roots most frequently affected are L4, L5 and S1
- table?
what are the investigations for lumbar spondylosis?
- MRI is the investigation of choice if available, since soft tissues are well imaged.
- Most patients with sciatica recover following conservative treatment with analgesia and early mobilisation; bed rest does not help recovery.
- The patient should be instructed in back-strengthening exercises and advised to avoid physical manoeuvres likely to strain the lumbar spine.
- Injections of local anaesthetic or corticosteroids may be useful adjunctive treatment if symptoms are due to ligamentous injury or joint dysfunction.
- Surgery may have to be considered if there is no response to conservative treatment or if progressive neurological deficits develop.
- Central disc prolapse with bilateral symptoms and signs and disturbance of sphincter function requires urgent surgical decompression – Cauda equina syndrome.
- A central lumbosacral protrusion should be suspected if a patient with back pain develops retention of urine or sacral numbness. Urgent imaging and surgical decompression is indicated for this emergency.
what is cauda equina syndrome?
- a serious neurological condition in whcih damage to the cauda equina causes acute loss of function of multiple roots (below L1 or L2) of the lumbar plexus
what causes cauda equina syndrome? how can it be treated?
can be caused by compression by a central disc or compression/trauma/damage of the cauda equina region
can be treated by surgical decompression
what are the signs and symptoms of cauda equina syndrome?
- severe back pain
- saddle anaesthesia: this is anaesthesia or paraesthesia involving S2 ot S5 dermatomes, including the perineum, external genitalia and anus - a ‘pins-and-needles’ sensation of the groin and inner thighs is felt
- if the deficits begin at S2 roots and below, there may be no obvious leg weakness
- involvement of the S2, S3 and S4 nerve roots can produce a distended atonic bladder with urinary retention or overflow incontinence, constipation, decreased rectal tone, faecal incontinence, and loss of erections
Essential to detect and treat cauda equina syndrome promptly to avoid irreversible deficits
how serious is spinal cord compression?
The early stages of damage are reversible but severely damaged neurons do not recover; hence the importance of early diagnosis and treatment.
what are the symptoms of spinal cord compression?
the onset of symptoms is usually slow (over weeks), but can be acute:
- pain = localised over the spine or in a root distribution, which may be aggravated by coughing, sneezing or straining
- paraesthesia/’pins-and-needles’ = numbness or cold sensations, especially in the lower limbs, which spread proximally, often to a level on the trunk
- motor weakness = heaviness or stiffness of the limbs, most commonly the legs
- urgency or hesitancy of micturition, leading eventually to urinary retention
• Pain and sensory symptoms occur early, while weakness and sphincter dysfunction are usually late manifestations.
• The signs vary according to the level of the cord compression and the structures involved:
Involvement of the roots at the level of the compression may cause dermatomal sensory impairment and corresponding lower motor signs.
Interruption of fibres in the spinal cord causes sensory loss and upper motor neuron signs below the level of the lesion, and there is often disturbance of sphincter function. The distribution of these signs varies with the level of the lesion.
what imaging is used for spinal cord compression?
MRI
what are the different surgical approaches to the spine? when urgent, semiurgent and elective?
- Discectomy: surgical removal of part (partial discectomy) or all (total discectomy) of a diseased or damaged intervertebral disc. It is performed for the relief of neurological symptoms arising from a displaced intervertebral disc or as part of a more extensive procedure.
- Laminectomy: surgical cutting into the backbone to obtain access to the vertebral (spinal) canal. The surgeon excises the rear part (the posterior arch) of one or more vertebrae. The operation is performed to remove tumours, to treat injuries to the spine, such as prolapsed intervertebral (slipped) disc (in which the affected disc is removed), or to relieve pressure on the spinal cord or roots.
- Foraminotomy: is a medical operation used to relieve pressure on nerves that are being compressed by the intervertebral foramina, the passages through the bones of the vertebrae of the spine that pass nerve bundles to the body from the spinal cord. The impinging bone or disk material is removed.
- Indications for urgent surgery include the rare instances in which cord compression or cauda equine syndrome occurs.
- Semiurgent surgery is indicated in patients with progressive or severe motor deficits or in the occasional patient with intolerable, medically intractable pain.
- Elective surgery is contemplated when a clear radiculopathy is present and conservative measures such as rest, physical therapy, and traction have been tried for 1 to 3 months but were ineffective.
what is radiculopathy?
This refers to a set of conditions in which one or more nerves is affected and does not work properly (a neuropathy). The emphasis is on the nerve root (radix = “root”). This can result in pain (radicular pain), weakness, numbness, or difficulty controlling specific muscles.
what happens with transverse cord lesions?
- all sensory and motor pathways are either partially or completely interrupted
- there is often a sensory level, meaning diminished sensation in all dermatomes below the level of the lesion
- the pattern of weakness and reflex loss can also help determine the lesion’s spinal cord level
what Brown-Sequard syndrome (hemicord syndrome)?
• Damage to the lateral corticospinal tract causes ipsilateral upper motor neuron–type weakness.
• Interruption of the posterior columns causes ipsilateral loss of vibration and proprioception.
• Interruption of the anterolateral systems, however, causes contralateral loss of pain and temperature sensation.
This often begins slightly below the lesion because the anterolateral fibres ascend two to three segments as they cross in the ventral commissure.
There may also be a strip of one or two segments of sensory loss to pain and temperature ipsilateral to the lesion, caused by damage to posterior horn cells before their axons have crossed over.
what happens with posterior cord syndrome?
- Lesions of the posterior columns cause loss of vibration and position sense below the level of the lesion.
- With larger lesions, there may also be encroachment (impingement) on the lateral corticospinal tracts, causing upper motor neuron–type weakness.
what happens with anterior cord syndrome?
- Damage to the anterolateral pathways causes loss of pain and temperature sensation below the level of the lesion.
- Damage to the anterior horn cells produces lower motor neuron weakness at the level of the lesion.
- With larger lesions, the lateral corticospinal tracts may also be involved, causing upper motor neuron signs.
- Incontinence is common because the descending pathways controlling sphincter function tend to be more ventrally located.
what is the difference between and upper and lower motor neurone lesion? what are the different signs?
Upper motor neurone:
- Indicate that the lesion is above the anterior horn cell (i.e. spinal cord, brain stem, motor cortex).
- Are characterised by increased muscle tone (spasticity), weakness (generally flexors weaker than extensors in the legs and the reverse in the arms - pyramidal pattern of weakness), increased reflexes, an up-going plantar response and sustained clonus (a few beats is normal).
- Can be further localised by the other symptoms that go along with the weakness. For example:
- A cord lesion may also cause sphincter symptoms, a sensory level, bilateral motor signs.
- A brain stem lesion may also cause dysarthria, dysphagia, Horner’s syndrome, cerebellar signs, spinothalamic sensory loss.
- A lesion of the motor cortex may be associated with frontal signs, dysphasia, hemianopia, disturbance of higher sensory function eg agnosias.
lower motor neurone:
- Indicate that the lesion is either in the anterior horn cell or distal to the anterior horn cell (i.e. anterior horn cell, root, plexus, peripheral nerve).
- Characterised by decreased muscle tone, weakness and wasting (atrophy) in the muscle(s) supplied by that motor nerve, arreflexia (absence of the relevant reflex - the motor nerve is the efferent arm of the reflex arc), muscle fasciculations.
- Again the level of the problem can generally be inferred from accompanying symptoms and signs, for example:
- Back pain and sciatica suggests a root problem
- Weakness of the biceps with absence of the biceps reflex, with upper motor neurone signs in the legs suggests cord disease (eg a disc) at C5/6 (LMN at that level, UMN below).
- Weakness of thumb abduction, wasting of the thenar eminence and numbness in the thumb and lateral 21/2 fingers suggests median nerve pathology.
how do opioids work? how can their toxicity be treated?
- Opioids work by combining with opioid receptors in the brain and spinal cord.
- This blocks the transmission of pain signals sent by the nerves to the brain.
- Although the cause of the pain may still remain, but less pain is felt.
- Their toxicity can be treated with naloxone or naltrexone (opioid receptor antagonist).
what are the different types of opioid receptors?
There are 4 types of opioid receptors – these mediate the main effects of opiates:
1. Mu (μ) receptors - are thought to be responsible for most of the analgesic effects of opioids, and for some major unwanted effects.
These are located in the brain, spinal cord, peripheral sensory neurons and intestinal tract. THIS IS THE RECEPTOR (μ1) THAT WE NEED TO LEARN!
μ1 = analgesia, physical dependence (this is an unwanted effect, where chronic use of the opioid produces tolerance. The negative physical withdrawal symptoms result from the abrupt discontinuation or dosage reduction).
μ2 = respiratory depression, miosis (constriction of pupil), euphoria, reduced GI mobility, physical dependence.
μ3 = possible vasodilation.
- Delta (δ) receptors result in analgesia but can also be proconvulsant.
These are located in the brain and the peripheral sensory neurons.- δ1 and δ2 = analgesia, antidepressant effects, convulsant effects, physical dependence.
- Kappa (κ) receptors contribute to analgesia at the spinal level and produce relatively few unwanted effects and do not contribute to dependence.
These are located in the brain, spinal cord and the peripheral sensory neurons.- κ1, κ2, κ3 = analgesia, anticonvulsant effects, depression, hallucinogenic effects, diuresis, dysphoria, sedation, stress.
- Nociception receptors activation results in an antiopioid effect (supraspinal), analgesia (spinal), immobility and impairment of learning.
- ORL1 = anxiety, depression, appetite, development of tolerance to μ-opioid agonists.
what is cocodamol?
- side effects
• This is an opioid analgesic derived from morphine but less potent as a pain killer, less sedative and less toxic.
4. It is less likely to cause dependence as it causes little to no euphoria.
• It contains codeine + paracetamol.
• Side effects: constipation.
• It is a prodrug.
what is the mechanism of action of NSAIDs?
- Primary action is inhibition of arachidonic acid oxidation by the fatty acid COX enzymes (there are three isoforms: COX-1, COX-2 and COX-3).
- This inhibits the production of prostaglandins and thromboxanes.
- NSAIDs vary in the degree to which they inhibit each isoform of the COX enzyme.
- The anti-inflammatory action (and most analgesic actions) of NSAIDs are related to their inhibition of COX-2, while their unwanted effects – particularly those affecting the GI tract – are largely as a result of their inhibition of COX-1.
what are the therapeutic effects of NSAIDs? what causes them?
NSAIDs have 3 main therapeutic effects:
1. Anti-inflammatory effect – modification of the inflammatory reaction.
o This occurs as a result of a decrease in prostaglandin E2 and prostacyclin (PGI2).
o It reduces vasodilatation and, indirectly, oedema.
o Accumulation of inflammatory cells is not reduced.
2. Analgesic effect – reduction of certain types of (especially inflammatory) pain.
o It occurs as a result of a decrease in the production of prostaglandins that sensitise nociceptors (ORL1) to inflammatory mediators such as bradykinin.
o They are therefore effective in all conditions that are associated with increased local prostaglandin synthesis.
3. Antipyretic effect – lowering of body temperature when this is raised in disease.
o IL-1 releases prostaglandins in the CNS, where they elevate the hypothalamic set point for temperature control, thus causing fever.
o NSAIDs prevent this.
what are side effects of NSAIDs?
GI disturbance/ skin rashes/ prolonged bleeding (due to decreased thromboxanes)/ increase the likelihood of thrombotic events such as myocardial infarction by inhibiting prostaglandin (PG) I2 synthesis/ bronchospasm/ liver disorders.
what are side effects of NSAIDs?
GI disturbance/ skin rashes/ prolonged bleeding (due to decreased thromboxanes)/ increase the likelihood of thrombotic events such as myocardial infarction by inhibiting prostaglandin (PG) I2 synthesis/ bronchospasm/ liver disorders.
- Caution is required when using NSAIDs because of certain common side effects:
- These include gastrointestinal irritation and risk of gastrointestinal bleeding, renal toxicity, potential drug interactions
- Some selective COX-2 inhibitors have also been found to have cardiovascular side effects such as myocardial infarction, stroke and elevation of blood pressure
- NSAIDs must be used with caution in older patients with impaired renal function and heart failure
paracetamol
- how work
- why good
- compared to NSAIDs
- dose
- Selective, though weak COX-2 inhibitor.
- Paracetamol does not have gastric or platelet side effects.
- It has a weaker anti-inflammatory effect than the other NSAIDs.
- Sold in packs of 16 to reduce suicides – this strategy has been very successful.
- Dose = by mouth = 0.5-1g every 4–6 hours to a maximum of 4g daily.
what are TCAs? what are examples?
- This is used to treat depression and neuropathic pain.
* E.g. imipramine, desipramine, amitriptyline, nortriptyline, clomipramin.
what is the mechanism of action for TCAs? what causes improvement in emotional and biological symptoms?
- The main immediate effect of TCAs is to block the reuptake of amines by nerve terminals, by competition for the binding site of the amine transporter.
- Most TCAs inhibit noradrenaline and 5-HT reuptake but have much less effect on dopamine reuptake.
- Improvement of emotional symptoms refelects mainly an enhancement of 5-HT-mediated transmission.
- Whereas relief of biological symptoms results from the facilitation of noradrenergic transmission.
what are side effects of TCAs?
- In addition to their effects on amine uptake, most TCAs affect other receptors, including muscarinic acetylcholine receptors (antagonist), histamine receptors and 5-HT receptors.
- The antimuscarinic effects of TCAs do not contribute to their antidepressant effects but are responsible for various side effects.
- In non-depressed patients, TCAs cause sedation, confusion and motor incoordination.
- These effects occur also in depressed patients in the first few days of treatment, but tend to wear off in 1-2 weeks as the antidepressant effect develops.
• Other side effects include:
Atropine-like effects include dry mouth, blurred vision, constipation and urinary retention/ Postural hypotension/ Sedation.
what happens with overdose of TCAs? what do usual therapeutic doses of TCAs increase risk of?
- TCAs, particularly in overdose, may cause ventricular dysrhythmias associated with prolongation of the QT interval.
- Usual therapeutic doses of TCAs increase the risk of sudden cardiac death.
- Dangerous in acute overdose: confusion and mania, cardiac dysrhythmias.
interactions of TCAs?
Liable to interact with other drugs (e.g. alcohol, anaesthetics, hypotensive drugs and non-steroidal anti-inflammatory drugs; should not be given with monoamine oxidase inhibitors).
what is gabapentin? dose?
- This is an anticonvulsant drug used to treat partial epilepsy and neuropathic pain, including peripheral neuropathy.
- Dose = 300mg once daily on day 1, 300mg twice daily on day 2, 300mg thrice daily on day 3.
what is the mechanism of action of gabapentin?
- GABA is a neurotransmitter in the CNS, involved with neuronal excitability.
- Gabapentin interacts with cortical neurons at auxillary subunits of voltage-sensitive calcium channels.
- Gabapentin increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters (catecholamines).
what are the side effects of gabapentin?
GI disturbances, dizziness, drowsiness
what is the WHO analgesic ladder?
o Mild pain: non-opioid, e.g. paracetamol, ± adjuvant
o Moderate pain: simple analgesic, e.g. paracetamol, + weak opioid, e.g. codeine
o Severe pain: strong opioids, e.g. morphine, ± non-opioid ± adjuvant
- A patient with mild pain is started on a non-opioid analgesic drug, e.g. paracetamol.
- If the maximum recommended dose is not sufficient or the patient has moderate pain, a weak opioid, e.g. codeine is added.
- If adequate pain relief is still not achieved with the maximum recommended dosages or if the patient has severe pain, a strong opioid is substituted for the weak opioid.
• It is important not to move ‘sideways’ (change from one drug to another of equal potency) on a particular step of the ladder.
what is TENS? how does it work?
- This is the introduction of pulses of low-voltage electricity into tissue for the relief of pain.
- It works by means of a small portable battery-operated unit with leads connected to electrodes attached to the skin; the strength and frequency of the pulses, which prevent the passage of pain impulses to the brain, can be adjusted by the patient.
- The electrodes are often placed on the area of pain or at a pressure point, creating a circuit of electrical impulses that travels along nerve fibres.
• In TENS, electrodes are used to activate large-diameter afferent fibers that overlap the area of injury and pain.
• Stimulation of the dorsal columns via surface electrodes presumably relieves pain because it activates large numbers of Aβ fibers synchronously.
• TENS machines are thought to work in two ways:
1. A high pulse rate triggers the ‘pain gate’ to close.
2. A low pulse rate stimulates the body to make its own endorphins.
what is a pain management programme?
“a psychologically based rehabilitation programme delivered in a group setting by an interdisciplinary team, the core members of which are a Clinical Psychologist, a Physiotherapist and a Medical Practitioner”.
what is a pain management programme?
“a psychologically based rehabilitation programme delivered in a group setting by an interdisciplinary team, the core members of which are a Clinical Psychologist, a Physiotherapist and a Medical Practitioner”.
• The programme works in synergy with CBT to teach how to live successfully with pain.
what is computerised tomography (CT)?
• Developed directly from conventional X-ray technology and therefore shares many of the same principles.
• Like conventional X-ray radiographs, CT scans measure density of the tissues being studied.
• There are really only two differences from conventional X-rays:
1. Rather than taking one view, the X-ray beam is rotated around the patient to take many different views of a single slice of the patient; hence the term “tomography”.
2. The X-ray data acquired in this way are then reconstructed by a computer to obtain a detailed image of all the structures in the slice (including soft tissues, liquid, and air, as well as bone); hence the term “computerized.”
how is MRI done? what are the two different ways?
- Image contrast may be weighted to demonstrate different anatomical structures or pathologies.
- Each tissue returns to its equilibrium state after excitation by the independent processes of T1 (spin-lattice) and T2 (spin-spin) relaxation.
T1 weighted image:
• This image weighting is useful for assessing the cerebral cortex, identifying fatty tissue, characterising focal liver lesions and for post-contrast imaging.
• In T1-weighted images, water appears dark, while fatty tissues appear bright.
- Thus, T1-weighted images have the appearance of anatomical brain sections, with CSF appearing dark, gray matter appearing gray (higher water content), and white matter appearing white (higher lipid content).
• The resolution of fine anatomical detail can usually be seen better with T1-weighted images.
T2 weighted image:
• This image weighing is useful for detecting oedema, revealing white matter lesions and assessing zonal anatomy in the prostate and the uterus.
• In T2-weighted images, on the other hand, water appears bright, and lipid appears dark.
- Thus, CSF appears very bright; areas of brain oedema, gliosis and gray matter are bright but somewhat less so than CSF; and myelinated areas appear dark.
• T2-weighted images usually make regions of brain abnormalities appear bright and easier to see than on T1.
• However, one pitfall of T2-weighted images is that bright-appearing CSF can obscure pathology located in the parenchyma adjacent to the ventricles or pia.
what are the advantages of an MRI scan?
- MR distinguishes between white and grey matter in the brain and cord.
- Cord and nerve roots are imaged directly.
- Pituitary imaging.
- MRI has resolution superior to CT.
- No radiation is involved.
- MR angiography (MRA) images blood vessels without contrast.
- MR images soft tissues.
- Tumours, infarction, haemorrhage, MS plaques, posterior fossa, foramen magnum and cord are demonstrated well by MRI.
MRI vs. CT
- what’s better for what
- what’s used when
- MRI provides high-contrast imaging of the nervous system in striking anatomical detail. It is therefore the imaging method of choice for detecting low-contrast or small lesions such as multiple sclerosis plaques, and so on.
- In addition, unlike CT scanning, in which the dense bones at the base of the skull obscure the adjacent areas with “shadowing” artifact, MRI provides remarkably clear images of crucial basilar structures such as the brainstem, cerebellum, and pituitary fossa. The spinal cord is also more clearly visible on MRI for similar reasons.
- MRI has its disadvantages as well. The main drawbacks are time, cost, and inferior performance in imaging fresh hemorrhage and bony structures.
- Also, MRI cannot be done in patients with cardiac pacemakers, certain other devices, or metallic fragments in the heart or eye.
- A typical MRI scan takes about 20 to 45 minutes to complete, while a quick CT scan in an unstable patient can be done in 5 to 10 minutes.
- In summary, CT is the preferred technique for patients with head trauma or suspected intracranial hemorrhage and as a first screening method to detect most intracranial lesions, especially in the emergency setting.
- MRI is better for patients who, on the basis of the clinical story, are suspected of having low-contrast lesions or brainstem or skull-base lesions, or as a secondary technique when a lesion is suspected that was not visible on CT. In non-urgent situations, in which a single, more definitive imaging method is desired, MRI is often the test of choice.
what is pain?
“an unpleasant sensory and emotional experience associated with actual or potential tissue damage”.
what is the primary focus of psychosocial approaches?
it’s to target influences on the pain experience (CBT)
what is catastrophising? how predictor of pain? how lead to disability?
• This is the exaggerated negative orientation toward pain…where a relatively neutral event is irrationally made into a catastrophe.
• A robust pain predictor:
1. Rumination- a focus on threatening information, both internal and external
2. Magnification- overestimating the extent of the threat
3. Helplessness- underestimating personal and broader resources that might mitigate the danger and disastrous consequences.
- Extremely negative thoughts about one’s plight, even with minor problems being interpreted as major catastrophes – catastrophising and consequently adaptive coping strategies are important in determining one’s reaction to pain – greater catastrophising and feeling a lower sense of control are among the most important predictors of chronic back pain
- catastrophising results in sensitisation of peripheral mechanisms of biological pain alarm system and thus results in greater pain
injury/strain -> pain - (catastrophic misinterpretations) > defense avoidance attention -> disuse -> disability
what is the fear-avoidance model for pain?
- Activities/ roles reduced
- Disengagement
- Depressed pattern of behaviour emerges
- Withdrawn/ worthlessness/ hopelessness
- Choose to avoid activities/ increased constraints
- Reduced positive activities
- Pain dominates most efforts
what are the theories behind increasing disparity in mortality rates between social classes?
- Cultural/behavioural explanation
• This stresses individual or lifestyle differences rooted in personal characteristics and levels of education, which influence behaviour and are, therefore, open to alteration through health-education inputs leading to changes in health behaviour. - Materialist of structuralist explanation
• These emphasize the role of economic and associated socio-structural factors, for example, the labour and housing markets, in the distribution of health and well-being.
• Supporters of this explanation believe that social structure is characterized by permanent social and economic inequality, which exposes individuals to different probabilities of ill health and injury:
Poor-quality and damp housing has been associated with worse health.
Low socio-economic status, low pay, and insecurity produce inadequacies in diet. - Social selection
• These argue that the occupational class structure is seen to act as a filter or sorter of human beings, and one of the major bases of selection is health: physical, strength, vigour, or agility. In this hypothesis, health determines social class. - Artefact explanation
• This suggests that both health and class are artificial variables produced by attempts to measure social phenomena and that; therefore, the relationship between them may itself be an artefact – an accidental effect – of little significance.
The materialist/structural hypothesis is favoured.
what causes traditional sciatic symptoms?
The sciatic nerve does not actually attach to the spinal cord directly. Instead, 5 pairs of spinal nerve roots converge to form the sciatic nerve in the pelvic region. These are the structures which can be compressed to elicit traditional sciatica symptoms.
how does pain normally get through the gate?
• Small nerve fibres (pain receptors) and large nerve fibres (normal receptors) synapse and large nerve fibres (‘normal’ receptors) synapse on projection cells, which go up the spinothalamic tract to the brain and inhibitory interneurons within the dorsal horn
• The interplay among these connections determines when painful stimuli go to the brain:
1. When no input comes in, the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed)
2. Normal somatosensory input happens when there is more large-fibre stimulation (or only large-fibre stimulation) – both the inhibitory neuron and the projection neuron are stimulated, but the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed)
3. Nociception (pain reception) happens when there is more small-fibre stimulation or only small-fibre stimulation – this inactivates inhibitory neuron and the projection neuron sends signals to the brain informing it of pain (gate is open)
what are the different theories of disability?
Medical model:
- Viewing disability as a problem of the person, directly caused by disease, trauma or other health condition, which therefore requires sustained medical care provided in the form of individual treatment by professionals
- Management of the disability is aimed at a ‘cure’ or the individual’s adjustment and behavioural change
- Medical care viewed as the main issue
Social model:
- Sees the issue of ‘disability’ as a socially created problem and a matter of the full integration of individuals into society
- Management of the problem requires social action and is the collective responsibility of society at large to make the environmental modifications necessary for the full participation of people with disabilities in all areas of social life
describe the arrangement of the peripheral nervous system
Cranial nerves = 12 pairs
- 2 from the forebrain
- 8 from brainstem
- some cranial nerves are motor, some sensory and some mixed, and some carry parasympathetic fibres as well
Spinal nerves = 31 pairs
- always carry both sensory and motor fibres
- we don’t name the spinal nerves
describe the arrangement of grey matter in the spinal cord
- Dorsal horn
- Lateral horn
- Ventral horn
- Rexed’s laminae – grey matter divided into 10 of these
Grey matter is mostly nerve cell bodies – in ventral horn there’s the cell bodies of motor neurones, in the dorsal horn there’s sensory neurones and in lateral horn there’s sympathetic or parasympathetic neurones (autonomic)
general sensory pathway
1st order neurone – remains ipsilateral and terminates in spinal cord (body in dorsal root ganglion) or medulla
2nd order neurone arises in spinal cord or medulla, it decussates and terminates in the contralateral thalamus
3rd order neurone arises in thalamus and terminates in sensory cortex
what would happen if you got a upper or motor neurone lesion in terms of muscles in the face?
- So, if you got an upper motor neurone lesion, the muscles above the eye would still work but the muscles below your eye wouldn’t
- If you got a lower motor neurone lesion, it would involve taking out the whole nucleus itself, so you would lose activity on the whole of the face
describe parasympathetic and sympathetic pathways
PARASYMPATHETIC Brain stem (then associated with a cranial nerve – only 4 cranial nerves that have parasympathetic fibres – cranial nerves 3, 7, 9 & 10) or sacral spinal cord -> preganglionic neurone (these tend to be very long as they synapse very close to the organ they’re going to innervate) -> nicotinic receptor (acetylcholine released) -> postganglionic neurone -> muscarinic receptor (acetylcholine released) -> effector
SYMPATHETIC
Thoracic or lumbar spinal cord -> preganglionic neurone -> nicotinic receptor (paravertebral or prevertebral ganglion) (acetylcholine released) -> postganglionic neurone -> adrenoceptor (norepinephrine released) -> effector
NB: postganglionic sympathetic neurones acting on sweat glands release Ach which binds to muscarinic receptors
where does the sympathetic chain receive outflow from?
T1-L2
what is the root of every impulse through the sympathetic chain before it chooses 1 of 3 options?
- Nerve cell bodies of preganglionic neurones located in lateral horn of grey matter
- Axon passes in ventral root -> spinal nerve -> ventral rami -> white ramus communicates
what are TRP channels? what are a couple of examples?
- TRP channels: transient receptor potential channel
- TRPV1 = temperature sensitive channel – heat
- TRPM8 = temperature sensitive channel – cold
what are the different types of pain?
TYPES OF PAINS: 1) ACUTE NOCICEPTIVE
- High-threshold stimulus-dependent pain
- Thermal, mechanical or chemical stimuli
- Pain evoked in a graded response by appropriate high intensity (noxious) stimuli
= good pain!
- Adaptive and serves a protective purpose
TYPES OF PAINS: 2) INFLAMMATORY
e. g. when something feels sore afters, such as when you’ve broken an ankle
- Active inflammation
- Sensitisation
- Evoked by low and high intensity stimuli
- Adaptive, protective during the healing response & reversible
TYPES OF PAIN: 3) NEUROPATHIC ‘pain caused by a lesion or disease of the somatosensory nervous system - Marked neuroimmune component - Sensitisation - Spontaneous and evoked by low and high intensity stimuli = bad pain! - Maladaptive and persistent - Abnormal amplification - Serves no useful purpose - Often long-lasting - Not well-managed (maladaptive pain = unhelpful pain that tends to be out of all proportion to actual tissue damage and which persists long after the tissues have healed so that the pain becomes the problem, rather than the tissues from which the pain comes)
what are the different types of neuropathic pain?
- Traumatic e.g. nerve entrapment, injury
- Central e.g. stroke, spinal cord injury, MS
- Neurotoxic e.g. microtubule-stabilising agent (MTSA) – induced neuropathy
- Infectious e.g. HIV-neuropathy & post-herpatic neuralgia (after shingles)
- Metabolic e.g. diabetic neuropathy & alcohol-induced neuropathy
- Idiopathic – no known cause
what is the mechanism of neuropathic pain?
- Increase inflammatory cells and mediators in PNS & CNS
- Altered nociceptor activity (receptor/ion channel expression) – increased firing
- Altered spinal processing: sensitisation, synaptic reorganisation
- Altered central processing, descending inhibition
what does an increase in peripheral inflammatory mediators cause?
explain increased vascular permeability and cell recruitment.
describe altered sodium channel activity in neuropathic pain
INCREASE IN PERIPHERAL INFLAMMATORY MEDIATORS ELICITS SHORT AND LONG-TERM EFFECTS ON NEURONAL EXCITABILITY
- Direct receptor-mediated excitatory effects, e.g. histamine, TNFalpha
- Indirect roles include increased vascular permeability and increased cell recruitment
- Direct and indirect modulation of receptor and ion channels
INCREASED VASCUAR PERMEABILITY AND CELL RECRUITMENT
- Neutrophils are the first inflammatory cells to infiltrate damaged tissue – very fast at infiltrating
- Depletion of neutrophils following nerve injury -> decrease thermal hyperalgesia
- Neutrophils produce proinflammatory factors, e.g. TNFalpha and chemokines – attracts macrophages
- Amplification/sensitisation of primary afferents
ALTERED SODIUM CHANNEL ACTIVITY IN NEUROPATHIC PAIN
- Voltage-gated sodium channel genes are upregulated in injured sensory neurons – increased excitability/ectopic firing (in the absence of any stimulus)
- Important in pain?
- Channelopathies
- paroxysmal extreme pain disorder is caused by gain-of-function mutation in the Nav1.7 voltage-gated sodium channel
- rare mutations of the Nav1.7 gene causes a congenital insensitivity or indifference to pain
- Pharmacological blockade provides pain relief
- carbamazepine: trigeminal neuralgia
- lamotrigine: HIV sensory neuropathy and central poststroke pain
- topical lidocaine: PHN
describe route of pain processing
PAIN PROCESSING
- Spinal cord: pain pathways cross midline here
- Medulla: proprioceptive pathways cross midline here
- Thalamus: synapse of 2nd order neurones
- Cortex
CENTRAL PAIN PROCESSING
Sensory-discriminative component: (identifies the painful stimulus according to position, time and intensity)
Stimulus ->spinal cord -> thalamus -> somatosensory cortex or -> hypothalamus limbic system
->reticular formation -> hypothalamus limbic system (behavioural and emotional responses to pain)
which opioids are weak and which are strong?
weak = codeine, tramadol strong = morphine, oxycodone, fentanyl, methadone
which drugs are sodium channel blockers and can therefore be used to manage pain?
- local anaesthetics e.g. lidocaine
- antiepileptics e.g. carbamazepine
- TCAs e.g. amitriptyline
how do gabapentinoids work to manage pain?
they are calcium channel modifiers
what is used to treat acute vs. chronic pain?
- Acute – can be severe, but short-lived (paracetamol and/or NSAIDS, opioids)
- Chronic/pathological (antidepressants, anti-convulsants (used in treatment of epileptic seizures), opioids)
what’s the stepwise pharmacological mnagement of neuropathic pain?
1st
- Anticonvulsants e.g. gabapentin, pregabalin
- TCAs e.g. amytriptaline, duloxetine
2nd
- SSRIs e.g. paroxetine
- SNRIs
- Lidocaine
3rd
- OPIODS e.g. tramadol, capsaicin cream, combinatorial treatments
4th
- Others e.g. stronger opioids, cannabinoids, lamotrigine
what is the pathway of acute pain? the different stages?
- Transduction
- tissue damage results in the release of inflammatory mediators which bind to nociceptors converting a thermal, mechanical or chemical insult into an electrical signal - Transmission
- spinothalamic tract, spinoreticular tract, spinomesencephalic tract - Perception
- nociceptive traffic is filtered through the individual’s genetics, cognition, effect, environment and previous pain experiences - Modulation
- nociceptive traffic is modulated by excitatory and inhibitory effects on the somatosensory system
what causes modulation to pain?
- Cortical/subcortical impulses
- Impulses to the periaqueductal matter
- Locus coeruleus (noradrenergic inhibitory system)
- Raphe nucleus (serotonergic inhibitory system)
- Inhibitory synapses in the dorsal horn
- Ascending spinothalamic tract
- Motor neuron reflex
what is the mechanism of action for local anaesthetics?
- An injected local anaesthetic exists in equilibrium as a quaternary salt (BH+) and tertiary base (B)
- The proportion of each is determined by the pKa of the anaesthetic and the pH of the tissue
- The lipid-soluble species (B) is essential for penetration of both epineurium and neuronal membrane
- Once the molecule reaches the axoplasm of the neuron, the amine gains a hydrogen ion, and this ionised, quaternary form (BH+) is responsible for the actual blockade of the sodium channel
- Presumably it binds within the sodium channel near the inner surface of the neuronal membrane
how do different nerve fibres differ in sensitivity to local anaesthetic? what does this mean?
- Nerve fibres differ in their sensitivity to local anaesthetics
- Small nerve fibres are more sensitive than large nerve fibres while myelinated fibres are blocked before non-myelinated fibres of the same diameter
- Thus, the loss of nerve function proceeds as loss of pain, temperature, touch and proprioception, and then skeletal muscle tone
- This is why people may still feel touch but not pain when using local anaesthesia
what is the relationship between ketamine and opioids?
Ketamine is an adjuvant for opioids
is nociception pain?
no, pain is a brain perception
why do people get chronic pain?
- Pain that extends beyond the period of healing due to alteration in the processing of nerve signals and therefore has levels of identified pathology that often are low and insufficient to explain the presence and/or extend of the pain
- In chronic pain it is as if the useful changes that happen to the messaging system after an injury don’t ‘switch off’ even though healing has finished – the messages continue to be sent even though there is no more damage
- Chronic pain may also be defined as a persistent pain that disrupts sleep and normal living, ceases to serve a protective function and instead degrades health and function – unlike acute pain, chronic pain serves no adaptive purpose
what are the timings for acute and chronic pain?
Acute pain < 1 month
Chronic pain _> 3-6 months
what is malingering?
The conscious fabrication of symptoms to achieve some form of benefits such as attention, to be relieved of undesirable activities, to obtain prescription medication, or to qualify for disability compensation
what are pain behaviours?
Neither malingering nor symptom magnification are synonymous with pain behaviours – pain behaviours are non-conscious modes of communicating pain and distress and unlike cases of symptom magnification and malingering are not produced intentionally
how is chronic non-malignant pain classified?
- Neuropathic
- nerve injuries
- amputations
- stroke
- Nociceptive
- osteoarthritis
- rheumatoid arthritis
- migraine
- Generalised pain
- fibromyalgia
- MSK
- IBS
what is the biophyschosocial model of pain?
- Biological factors e.g. pain sensations/symptoms
- Psychological factors e.g. thoughts/beliefs, feelings/emptions (distress)
- Social environment e.g. family response/professionals’ response
what are the models of predictors of pain and disability?
- Resilience models – factors associated with a reduction in experience of pain, distress and disability
- acceptance, mindfulness, readiness for change, optimism, active coping, self-efficacy
- Vulnerability models – factors associated with an increased experience of pain, distress and disability
- anxiety, depression, fear of pain/re-injury, catastrophising, misattributions, somatic attention
why do antiepileptics and antidepressants work for pain management?
- Antiepileptics - reduce neurone excitability
- Antidepressants - raise serotonin and noradrenaline
- Both extremely non-specific approach
what are opioids?
synthetic durgs that produce opiate-like effects
what is heroin synthesised from?
morphine
describe:
- drug abuse
- drug dependence - physical
- drug dependence - psychological
- drug addiction
Drug abuse: substance used in a manner that does not conform to social norms. Can abuse drugs without being dependent or addicted. Drug dependence (physical): individual depends on drug for normal physiological functioning. Abstinence produces physical withdrawal symptoms. Drug dependence (psychological): acquiring and using drug are strong motivators of behaviour. Compulsive use. Drug addiction: not a clinical diagnosis. Typically used to emphasise psychological dependence. Idea that people can be physically dependent but not addicted.
what is substance use disorder diagnosed?
- Tolerance
- Withdrawal
- Continuing to use despite negative personal consequences
- Repeatedly unable to carry out major obligations
- Recurrent use in physically hazardous situations
- Continued use despite persistent or recurring social or interpersonal problems
- Using greater amounts or using over a longer time period than intended
- Persistent desire or unsuccessful efforts to cut down
- Spending a lot of time obtaining, using, or recovering
- Stopping or reducing important social, occupational, or recreational activities
- Consistent use despite persistent or recurrent physical or psychological difficulties
- Craving or a strong desire to use
2-3 = mild 4-5 = moderate 6-7 = severe
what’s the neurochemistry of reward? how doest his relate to addiction?
NEUROCHEMISTRY OF REWARD: MEASURING NEUROTRANSMITTERS IN THE VTA-NA PATHWAY
NA = nucleus accumbens
VTA = ventral tegmental area
NAcc (nucleus accumbens) dopamine rises with rewarding brain stimulation
NA dopamine increases in response to food and sex
Substances of abuse increase dopamine levels
ACUTE EFFECTS: ALL DRUGS OF ABUSE INCREASE DOPAMINE LEVELS IN NUCLEUS ACCUMBENS
- Directly or indirectly
Stimulants (cocaine, amphetamine) increase DA directly:
- Dopamine is normally released and taken back up by transporter
- Cocaine blocks this transporter, leading to increased dopamine levels
Dopamine system is modulated by other neurotransmitters:
- GABA – inhibitory on dopamine neuron
- Opiates inhibitory on GABA neuron
- So, opiates reduce the inhibition of dopamine so increase dopamine (allows stimulants to keep increasing DA)
what is tolerance at receptor level?
- Diminished response to drug – decreased effect or need more for same effect
- Changes in binding to receptors and/or changes in receptor processes and/or numbers
- Complex intracellular neural mechanisms, including opioid receptor desensitisation and down-regulation
- Need more opiate to release same amount of dopamine and get same ‘high’ or pain relief
what are the withdrawal symptoms on a time line?
Early withdrawal (8-24 hours after last use) Grade 1: - Lacrimation - Rhinorrhea - Diaphoresis - Yawning - Restlessness - Insomnia Grade 2: - Piloerection - Muscle twitching - Myalgia - Arthralgia - Abdominal pain Fully developed withdrawal (1-3 days after last use – most difficult) Grade 3: - Tachycardia - Hypertension - Tachypnoea - Fever - Anorexia - Nausea - Extreme restlessness Grade 4: - Diarrhoea - Vomiting - Dehydration - Hyperglycaemia - Hypotension - Curled-up position
Day 3:
- Severe anxiety
- Moderate depression
- Highest craving
- Nasal discharge
- Mydriasis
- Abdominal pain
- Diarrhoea
Day 10: - Moderate anxiety
- Subclinical depression
- Moderate craving
- Nasal discharge
Day 30: - Mild anxiety
- Mild depressive symptoms
- Milder craving
- Nasal discharge
what does cocaine do? what causes the withdrawal symptoms?
- Cocaine blocks reuptake carrier
- When you stop taking cocaine more dopamine is taken back up
- But you had normal dopamine to anyway because of chronic coke use
- So, when you stop you have less than the normal persons dopamine
what is used to prevent relapse? how work?
- agonist maintenance (methadone) – works very like heroine
- partial agonist maintenance (buprenorphine) – some similar effects
- antagonist maintenance (naltrexone) – opposite effects
SUBSTITUTION PHARMACOTHERAPY IN OPIATE ADDICTION
A: effects of opiates wanted by addicts – pleasure/reward
B: effect of opiates primary not wanted – respiratory depression
Ideal: give A, but not too much, without B
Methadone = full agonist (still some risk of B) Buprenorphine = partial agonist (little risk of B)
Naltrexone blocks the mu opiate receptor on GABA leading to reduced DA-ergic activity
- Reduced craving of drug
- But people don’t like it as people want the drug high
