Pain Exam 1: Witt-Enderby p1-24

4 types of pain?

nociceptive, inflammatory, neuropathic, functional

Nociceptive Pain

-pain associated with thermal, chemical, or mechanical ___ producing tissue ___

stimuli, damage

Nociceptive Pain

-this type of pain is important to get the person's ___ through a physiological ___ to protect the injured limb or tissue to promote healing

attention, sensation

Nociceptive Pain

-is therapy targeted for this type of pain?

yes

Steps of pain response

____ → ____ → ____ → ____ → ____

Transduction, Conduction, Transmission, Perception, Modulation

Nociceptive Pain

1- Transduction: stimuli (like heat, cold, etc.) release mediators, which activate _____ which act as a “___ of receptors”

nociceptors, hub

Nociceptive Pain

2- Conduction: The electrical signal travels as an action potential from the ___ to the ___

PNS, CNS

The electrical signal travels as an action potential from the PNS to the CNS through the ___ ___ ___

dorsal root ganglion

Nociceptive Pain

3- Transmission: The pain signal goes through the spinal cord; the key neurotransmitters are ___ and ___ ___

Glutamate, Substance P

Nociceptive Pain

4- ____ and ___ occur in the brain

perception, modulation

Inflammatory Pain

-follows the same steps (Transduction → Conduction → Transmission → Perception → Modulation)

-the difference is that in transduction, the nociceptors are activated by the release of mediators from ___ cells (like macrophages, mast cells, neutrophils) in damaged tissues

immune

Inflammatory Pain

-causes ___ in the body

inflammation

Inflammatory Pain

-is therapy targeted for this type of pain?

yes

Neuropathic Pain

-pain that arises due to damage of or compression to those ___ involved in mediation pain throughout the CNS

neurons

Neuropathic Pain

-damage to the neurons can be caused by stroke, AIDS, cancer, diabetes, and ___

trauma

Neuropathic Pain

-therapy is not targeted, and involves ___ ("trial and error")

polypharmacy

Neuropathic Pain

-in transduction, there is no stimuli (feeds); the pain arises from peripheral nerve ___

damage

Functional Pain

-not associated with any deficiency in the PNS or neurological defect

-etiology not clear, but may be due to food ___, hypersensitized neurons due to past ___/injuries, genetic predisposition, or psychological stress

allergy, infections

Functional Pain

-examples of conditions associated with this type of pain include ___, ____, or __-type headache

fibromyalgia, IBS, tension

Functional Pain

-therapy is not targeted, and involves a ____ approach

personalized

Modulation occurs through ____ modulatory pathways that act on the spinal cord. Key neurotransmitters in these pathways include ___ (NE) and ___ (5-HT)

descending, norepinephrine, seratonin

Descending → traveling ___ from the brain to the spinal cord

down

Types of pain stimuli:

1) pain due to external factors either ____ (radiation, heat, fall, electrical burn, etc) or ___ (conflict or difficulty in life, psychogenic pain)

physical, psychological

Types of pain stimuli:

2) pain due to ___, swelling, and/or microorganisms

inflammation

Types of pain stimuli:

3) pain due to ____ factors (impaired blood flow, tumor, spasm, decreased movement, etc)

internal

The goal of pain management is to ___ one's functioning while ___ pain without impeding the healing process

maximize, minimizing

The goal of pain management is to maximize one's functioning while minimizing pain without impeding the healing process. Does this mean we reduce pain to a level of "0"?

No

We do not reduce pain to a level of 0 because this would ____ the person from performing daily tasks and independent living. We want pain to be tolerable and promote good quality of life.

prevent

What are the 5 steps of nociceptive pain?

transduction, conduction, transmission, perception, modulation

1) Transduction = conversion of noxious stimuli (like thermal, mechanical chemical) into ___ activity in the peripheral terminals of nociceptor sensory fibers

electrical

Specifically, transduction takes energy in the form of mechanical, electrical, or chemical and converts it into molecules like ___, ____, ___, and ___ like H+ or K+ that can interact with receptors locates on neurons

bradykinin, prostaglandins, histamine, ions

The receptors located on neurons that interact with the molecules are called ____

nociceptors

2) Conduction = passage of action potentials from ___ to ___ via ___ __ ___ (ie dorsal horn)

PNS, CNS, dorsal root ganglion

In conduction, there are 2 types of neurons that act as a "___" for these nociceptors, and they are named based on the type of pain they are conducting (acute or chronic)

hub

Conduction Neuron Types:

1) A-delta fiber (conducts ___ pain)

2) C-fiber (conducts __ pain)

3) A-beta fiber (conducts light touch/proprioception)

acute, chronic

A-delta fiber

-acute pain

-____ myelinated

-___ conduction of action potentials (4-30m/sec)

-____ of the 2 neurons

lightly, fast, larger

C-fiber

-chronic pain

-___-myelinated

-___ conduction of the action potentials (1m/sec)

-___ of the 2 neurons

non, slower, smaller

3) Transmission = synaptic transfer from one neuron to the next through the release of neurotransmitters (like ___ and __ ___)

glutamate, substance P

Transmission is the ___ of the activation of the nociceptor by molecules and conduction of the action potentials down the axons of the A-delta or C-fiber

consequence

Steps that lead to transmission

1) first, there needs to be enough "______" of the nociceptors by bradykinin, prostaglandins, histamine, K+ or H+, etc during (transduction)

stimulus

Steps that lead to transmission

2) the stimulus of nociceptors causes an electrical "spike" to occur, which opens the receptor "___," triggering the influx of ____ to cause an excitatory post-synaptic potential

gate, Na+

epsp= ___ ___-___ ___

excitatory post-synaptic potential

Steps that lead to transmission

3) if the epsp is strong enough, it will depolarize the neuron and cause an electrical "spike" to occur, which generates an ___ ___

action potential

Steps that lead to transmission

4) the wave of Na+ entry/depolarization rushes down the length of the neuron (axon) towards the ___-synaptic membrane (conduction)

pre

Steps that lead to transmission

5) At the presynaptic-membrane, the wave of depolarization causes packets of neurotransmitters (like calcitonin gene-related peptide, aspartate, ___ and ___ ___ ) to be released into the synaptic cleft (transmission)

glutamate, substance P

Steps that lead to transmission

6) these neurotransmitters (primarily glutamate, and substance P) will ______ to their respective receptors on post-synaptic neurons to "transmit" the pain response

bind

Glutamate binds to ____ receptors (N-methyl-D-aspartate receptors) on the postsynaptic neuron during pain transmission in the spinal cord.

NMDA

Substance P binds ____ (neurokinin receptor type 1) receptors in the dorsal horn during pain transmission

NK1R

Blocking voltage-gated __+ or ___2+ channels reduces action potential propagation, leading to decreased release of ____ and ___ __, thereby reducing pain transmission.

Na, Ca, glutamate, substance P

Pain medications that target Na⁺ or Ca²⁺ channels and reduce pain include ___, ____, and ___.

gabapentin, pregabalin, lidocaine

4) Perception = how the mind ___ the pain; factors in environment, genetics, and mental state

perceives

The ___ pathway is the main pathway responsible for pain perception

spinothalamic

the ____ cortex and the ___ ___ cortex are involved in the localization of pain (determine the specific body part that is injured)

somatosensory, secondary somatosensory

the ____ ____ cortex and the ___ cortex are involved in the perception of pain

anterior cingulate, insular

The _____ functions not only as a "switching station" (meaning it determines where the signal will go next) but also has an important role in certain chronic pain conditions

thalamus

The brain is able to keep storage of memory recall of the ___ and __ components of pain that is long past

sensory, affective

5) Modulation = body's response to pain "perception" to modulate descending efferents and release ___ or ___ and impact neuronal signaling

norepinephrine, serotonin

Modulation

-occurs in brainstem via amplification of descending ____ neurons from the periaqueductal gray

inhibitory

TCAs, SNRIs, and endocannabinoids (THC, CBD) reduce pain by enhancing the ____ that occurs in the brainstem

modulation

Modulation

-can occur in cortex via cognitive ____ (distraction, hypnosis, expectation)

manipulations

Overall approaches to managing pain

-What 2 drug classes reduce pain by blocking inflammation during the transduction step?

NSAIDs, glucocorticoids

Overall approaches to managing pain

-What 4 drugs reduce pain by blocking peripheral pain neurons via decreasing impulses and transmitter release?

anti-convulsants, capsaicin, endocannabinoids (THC, CBD), benzodiazepines

Overall approaches to managing pain

-What 2 drugs are used for depression and work by increasing serotonin (5-HT) and/or norepinephrine (NE) levels in the CNS by blocking their reuptake?

SSRIs, SNRIs

Overall approaches to managing pain

-What 2 drugs work by blocking impulses to the brain?

NK1R antagonist, NMDA antagonist

Overall approaches to managing pain

-What drug reduces the perception of pain?

opiods

4 Steps of the inflammatory response

1) _____ occurs and ___ is released

damage, histamine

4 Steps of the inflammatory response

1) damage occurs and histamine is released

2) ___ response is activated (phagocytes and clotting factors)

immune

4 Steps of the inflammatory response

1) damage occurs and histamine is released

2) immune response is activated (phagocytes and clotting factors)

3) phagocytes ___ bacteria, dead cells, and cellular debris

engulf

4 Steps of the inflammatory response

1) damage occurs and histamine is released

2) immune response is activated (phagocytes and clotting factors)

3) phagocytes engulf bacteria, dead cells, and cellular debris

4) platelets move out of capillary to ___ wound, stop bleeding, and promote healing

seal

Glucocorticoids are used to block inflammation and include:

1) ____

2) ____ (most potent)

3) prednisolone

4) methylprednisolone

prednisone, dexamethasone

NSAIDs are used to block inflammation and include:

1) ____

2) ____

3) ketorolac tromethamine

-note NOT acetaminophen

ibuprofen, naproxen

Arachidonic Acid Pathway of Inflammation

-all inflammation starts with ____ in the cell membrane

phospholipids

Arachidonic Acid Pathway of Inflammation

-all inflammation starts with phospholipids in the cell membrane, which then are converted by ____ to ___ ___

PLA2, arachidonic acid

____ block arachidonic acid, and are potent because since arachidonic acid is so far upstream, they block all downstream mediators

glucocorticoids

Arachidonic Acid Pathway of Inflammation

-arachidonic acid can be converted to ___ by COX

prostaglandins

____ block COX

NSAIDs

____ and ___ ___ inhibit prostaglandins and proinflammatory cytokines (TNF, IL-1, IL-6, IL-8, and NF-κB)

THC, oral dronabinol

____ (CBD) (brand name ____) inhibit proinflammatory cytokines by affecting the reuptake of adenosine

cannabidiol, epidiolax

Goal of treating pain: tone down the __-___ (acute pain) and ___ fibers (chronic pain)

A-delta, C

3 Pharmacologic approaches to treat pain:

1) prevent ___ __ or ___ from activating their receptors

2) enhance ____ neuronal inputs or block excitatory neuronal inputs into A-delta and C fibers

3) block ___ impulses going through pain neurons

SubP, glutamate, inhibitory, nerve

1. Approaches to prevent SubP and glutamate from activating their receptors

a) decrease ___ of SubP and glutamate

b) antagonize binding of SubP and glutamate to their ___

levels, receptors

Remember

SubP binds to ___ receptor

Glutamate binds to ___ receptor

NK1, NMDA

1a) Decrease the release of NT from nerve terminals

-what 2 drugs decrease the release of SubP?

capsaicen, CBD

Capsaicin and CBD both target the VR1 pre-synaptic ____ receptor

vanilloid

When Capsaicin and CBD activate the VR1 vanilloid receptor, this ___ subP, therefore ___ perception of pain

decreases, decreases

1a) Decrease the release of NT from nerve terminals

-what 2 drugs decrease the release of Glutamate?

THC/dronabinol, levitaracetam

THC/dronabinol and levitaracetam act on the VR1 pre-synaptic ____ receptor

vanilloid

THC/dronabinol and levitaracetam act on the VR1 pre-synaptic vanilloid receptor via ___ synaptic vesicle protein

SV2A

THC/dronabinol and levitaracetam modulate the VR1 pre-synaptic vanilloid receptor via SV2A synaptic vesicle protein, which ___ glutamate, which results in __ stimulation of NMDA receptors, which ___ the pain response

decreases, no, decreases

1b) antagonize binding of SubP and glutamate to their receptors

-what drug antagonizes the binding of SubP to NK1?

aprepitant

1b) antagonize binding of SubP and glutamate to their receptors

-what 2 drugs antagonize the binding of glutamate to NMDA?

ketamine, methadone

Ketamine is the most ___ NMDA receptor antagonist

potent

Ketamine is an irreversible or reversible NMDA receptor antagonist?

reversible

Ketamine binds the _____ site inside the NMDA receptor channel. and only binds when the channel is ___/activated

phencyclidine, open

2. Enhance inhibitory neuronal inputs into A-delta and C fibers

a) increase ____

b) increase ____

c) increase ____

GABA, NE, 5HT

Remember

More glutamate (+) → ____→ more pain :(

More GABA (-) → _____ → less pain :)

depolarization, hyperpolarization

2a) Enhance inhibitory neuronal inputs or block excitatory neuronal inputs into A-delta and C fibers

-we can decrease excitatory neuronal inputs (glutamate) with what 2 drugs?

ketamine, methadone

When NMDA receptor antagonists (methadone and ketamine) are given, they prevent glutamate from interacting with the ___ receptor, therefore ↓ subP and glutamate, therefore ↓ pain

NMDA

2a) Enhance inhibitory neuronal inputs or block excitatory neuronal inputs into A-delta and C fibers

-we can increase inhibitory neuronal inputs (GABA) with what class of drugs?

benzodiazepines

Benzodiazepines _____ with the GABA receptor to enhance its effect

synergize