6/12- Pharmacology of Pain Flashcards
What is pain?
Perception of an unpleasant sensation
- e.g. nociceptors are specialized Rs for noxious stimuli (sharp pricking, slow burning)
What kind of receptors are nociceptors (structurally)?
Free nerve endings
Are nerves transmitting pain myelinated or unmyelinated?
Can be either
What are the other (non-nociceptor) sensation receptors?
What type of R is each?
- Meissner’s corpuscle (mechanoreceptor)
- Pacinian corpuscle (pressure, vibration)
- Ruffini’s ending (mechanoreceptor)
- Merkel’s disk (mechanoreceptrs)
- Hair follicle receptor (mechanoreceptor)
How do sensory neurons modulate pain?
Sensory neurons release NTs that increase pain perception:
- This occurs in the periphery and also in CNS
- NT in periphery dilates BVs and sensitizes nerve endings
- Releases glu, CGRP, Sub P… in SC
What is CGRP? What does it do?
CGRP = Calcitonin Gene-Related Peptide (37 AAs)
- acts via Gs: cAMP -> EPSP (dilates BVs)
- acts via Gq: IP3/Ca (degranulation of mast cells -> histamine, which sensitizes nerve endings)
What are some different factors that facilitate pain perception?
- Prostaglandins (E2)
- Serotonin
- Histamine
- Bradykinin
- K+ from cell lysis
- ATP from cell lysis
- Substance P
- CGRP
- Endorphins (inhibit pain transmission/perception)
- Increase inhibition
What are some available drugs for modulating pain?
- Acetaminophen (Tylenol)
- NSAIDs (Ibuprofen, Naproxen, Indomethacin)
- Serotonin subtype agonists (Sumatriptan)
- Blockers not available; not effective but in development
- Morphine, codeine, etc. inhibit transmission/perception of pain
- Gabapentin, Pregabalin
Characteristics of Acetaminophen (Tylenol)?
- Functions
- Enters CNS (Y/N)
- Mechanism
Functions: analgesic and anti-pyretic, but very WEAK anti-inflammatory
Enters CNS! (good when used to relieve pain)
Mechanism: Inhibits COX (most say both, possibly just COX-2); prevents prostaglandin release that would sensitize sensory nerve endings in periphery and CNS (somewhat specific to PGs in context of inflammation without interfering much in housekeeping PGs)
Main ascending pain pathway?
Spinothalamic tract (STT)- sense pain, temperature, and crude touch
- Pain/temp sensed by free nerve terminals
- 1’ neuron synapses in SC ipsilaterally near level of entry (in dorsal horn)
- 2’ neuron decussates and ascends in lateral fasciculus to synapse in VPL of thalamus (ant white commissure)
- 3’ neuron projects to primary somatosensory cortex (post-central gyrus)
What are some other (indirect) Spino-thalamic pathways?
- Paleo-thalamic
- Spino-reticular
- Spino-mesencephalic
Basically, pain is also relayed to:
- Reticular formation
- Periaqueductal gray (PAG)
- Amygdala
- Cingulate gyrus, etc.
What does the ascending pathway release in PAG? Results in?
- Glutamate and Substance P
- Activates enkephalin interneurons in PAG
What is enkephalin? Where/how does it work?
Enkephalin = exogenous morphine
- In PAG, enkephalin inhibits GABA neurons projecting to midline raphe magnus
- Serotonergic pathway from Raphe magnus releases serotonin in SC
- Serotonin and NE activate enkephalin interneurons in dorsal horn
Thus: more NE/serotonin -> more GABA -> less pain
Morphine works in (1) PAG and (2) Dorsal horn to inhibit pain transmission
What two places does morphine work to inhibit pain transmission?
- PAG
- Dorsal horn of spinal cord
What is one of the main sites of pain modulation in the spinal cord?
Where 1’ neuron relays pain signals to 2’ neuron
- Raphe magnus nueuron (serotonin) an dpontine neuron (NE) release NTs onto enkephalin-containing interneuron
- Enkephalin interneuron releases onto opiate receptors on neuron synapse (this neuron also releases GABA)
So, altogether, what are all of the ways (3) pain pathways can be modulated?
1. Ascending path
- 1’ neuron releases glu, Sub P -> EPSP in 2’ neurons and pain signals are relayed
- More NT -> more pain signals
2. Descending paths
- Serotonin and NE excite interneurons containing enkephalins -> IPSP in axon terminals of 1’ neuron and dendrites of 2’ neuron
- Results in less glu/Sub P released and more difficult to excite 2’ neurons, so less pain is transmitted
3. Drugs given from outside
- Morphine/codeine/drugs that bind to opiate Rs and decrease relay of pain signals.
- Not a cure; problem still their, just decreased perception
Normally ___ depolarizes 2’ neuron to ____ (allow/inhibit) pain signals.
- Normally glutamate depolarizes 2’ neuron to allow pain signals
____ released by descending pathways (or morphine from outside) ____ (depol/hyperpol) both presynaptic and postsynaptic nerve cell membranes, resulting in _____.
Enkephalins released by descending pathways (or morphine from outside) hyperpolarize* both presynaptic and postsynaptic nerve cell membranes, resulting in reduced transmission of pain signals
*Voltage-gated Ca channels less likely to open
What is the treatment for heroin addiction?
Orally active methadone (long t1/2 = 2d!)
- Long half life compared to heroin (8 min)
- Remains in system for 10-60 hrs
