Lecture 17, 18: Pain Flashcards
Discriminative pain
Ability to perceive and localize
Affective pain
Behaviors and emotions that affect mood and motivation
Pain information is carried in which spinal tract? Which fibers? What thalamic nuclei?
Spinothalamic; Ad and C fibers; VPL and VPM (face)
Affective pain nuclei in pons
Parabrachial nucleus (ACh cells)
Affective pain nuclei in midbrain
Periaquaductal gray
Affective pain nuclei in thalamus
VM and MD (recieves a lot of limbic information, relays to PFC)
Affective pain nuclei in forebrain
Amygdala (fear), globus pallidus (mediates decision making)
Affective pain nuclei in hypothalamus
VMH
MD projects to…
Cingulate (and PFC)
VM projects to…
S1 and insula
Limbic system contributes what to pain? What structures?
Emotional content; amygdala/cingulate
Motor/cognitive systems contribute what to pain? What structures?
Motivation; GP, insula, cingulate, S1
Hypothalamus contribute what to pain? What structures?
Generation of appropriate beavhiors to threats; VMH
Descending systems contribute what to pain? What structures?
Transmission of nociceptive info back down to dorsal horn of spinal cord; amygdala, VMH, PAG, rostroventral medulla (parabrachial, LC, raphe)
What structure directly projects to the descending systems of the spinal cord?
PAG
Raphe and LC nuclei project to what kind of dorsal horn neuron? What do these projects to? Effect?
Local circuit inhibitory endogenous opioid neurons; Ad or C axons AND dendrites of neurons rising up the spinothalamic tract; diminish pain signal
General types of pain disorders (4)
Nociceptive, inflammatory, dysfunctional, neuropathic
Nociceptive pain
Physiological pain produced by noxious stimuli that achieves high-threshold nociceptor neurons, protective
What fiber mediates first pain? Second pain?
Ad; C
Why is visceral pain able to generate referred pain?
Cutaneous and visceral neurons carrying pain information converge on the same neuron in dorsal horn
Inflammatory pain; always require stimulus?
Pain hypersensitivty due to peripheral inflammation, adaptive and reversible (protects during healing); NO, pain at baseline AND a not necessarily a painful stimulus can worsen (allodynia and hyperalgesia)
Allodynia and how? (pathway)
Normally non-painful stimuli becomes painful (sunburn); Ab fibers and C fibers can both synapse on the same inhibitory local circuit neuron, which then synapses on spinothalamic system
Hyperalgesia and how? What is this phenomenon called?
Exaggerated response to a normally painful stimulus; enhanced synaptic signaling in dorsal horn between Ad/C fibers and spinothalamic tract; central sensitization
Dysfunctional pain; always require stimulus?
Same features as inflammatory pain, but w/out evidence of inflammation, neither protects nor supports healing (fibromyalgia); NO (can be spontaneous)
Neuropathic pain; always require stimulus?
Maladaptive plasticity caused by lesion/disease that alters nociceptive processing, can affect every stimulus in pain pathway, difficult to treat; NO
Phantom limb pain arises from…
Maladaptive reorganization of connections (plasticity/sprouting) in CNS centers, particularly S1
Treatments of neuropathic pain (4)
Antidepressants (enhances monoamine descending inhibitory control); anticonvulsants (block ectopic discharge and transmitter release); opioids (enhances endogenous opioid systems); cannabiniods (reduces pain-related activity in amygdala/cingulate); topical therapies (blast NTs out of pain pathways for temporary relief)
Difficulties in treating neuropathic pathways (2)
Synapses throughout CNS and PNS make targeting treatment difficult and opioids can co-opt reward pathways leading to addiction
Structural features of local anesthetics (3)
- Aromatic group (lipophilic); 2. Amino group (ionizable); 3. Linker region (amide vs ester)
Duration of local anesthetics depends on…
Lipophilicity (more lipophilic/longer chain, longer action)
How does benzocaine’s structure make it unique?
Non-ionizable, only topical
Molecular target of local anesthetics…Structure? Where does the drug bind and how?
VG-Na+ Channel; four domains w/ 6 transmembrane channels, S4 helices are voltage sensors that open w/ depolarization; binds w/in pore of channel from INTRACELLULAR side
What form of local anesthetic has higher affinity for Na+ pore?
Ionized
Most LAs are weak/strong bases/acids with pKas between…
Weak bases, 7.5 - 9
If the tissue pH is lower, what is the effect on LAs?
Less drug will be in the lipophilic form (less potent)
About what percent of LAs passe into the membrane? What route?
10%; “Intracelluar Route”
If a drug is only in uncharged form, what route? Major/minor? Require activity of cell?
Can diffuse INTO (not through) lipid bilayer and enter binding site = “Membrane Deliminated”; minor; cell does not have to be active
LAs require the cell to be…This is called?
Active (firing APs = open Na+ channel); “Use-dependent blockade”
T/F: Is the axon cell membrane the only barrier to the therapeutic binding site?
No! Epi/peri/endoneurium must also be transversed (requiring many transformations)
Relate potency and hydrophobicity
More hydrophobic accumulate in lipid bilayer = more potent (but slower)
What fiber type is the most sensitive to LAs?
C-type AND sympathetic post-ganglionic fibers (alpha receptors leading to vasodilation); Ad fibers also sensitive
Why is a vasoconstrictor administered with a LA?
Increases duration of effect and reduce systemic adverse effects
Esters are hydrolyzed by…why is this important? What are they metabolized into? Why is this important?
Pseudocholinesterases; metabolized locally so low risk of systemic effects; PABA = common hypersensitivty drug
Amides are hydrolyzed by what and where? Why important?
P-450 enzymes, liver (so require systemic circulation); greater risk of systemic effects, bad for pts with liver disease
Adverse effects of LAs: CNS
Sedation –> seizures and loss of consciousness
Adverse effects of LAs: cardiac
Block of cardiac Na+ channels (arrhythmias: AV-block; ventricular arrest)
T/F: Cadiac effects before CNS
False! CNS before cardio
Routes of administration of LAs
Topical, inject near a nerve (infiltration, field block, nerve block, epidural, spinal), regional block
Cocaine
Topical use on mucous membrane anesthetic, vasoconstrictor
Procaine (novocaine)
Infiltrate w/ low potency, slow onset, short duration
Tetracaine
Spinal block/topical w/ slow onset, but more potent/longer acting
Benzocaine
Non-ionzable, only surface
Lidocaine
Most common local anesthetic w/ rapid onset and high extraction by liver
Prilocaine
Side effect: methemoglobinemia (Fe3+ –> Fe2+ in hemoglobin)
Bupivacaine
Blocks sensory > motor neurons (good for labor)
Ropivacaine
Correct isomer of bupivacaine
