Week 09.14.20: Neuro I: Chronic Pain, Addiction & Mental Illness

Question 1

What are the steps of SYNAPTIC TRANSMISSION?

Answer 1

1. 1: Action potential travels down neuron
2. 2: Voltage-gated calcium channels open, allowing calcium to enter.
3. 3: Higher calcium levels cause neurotransmitter (NT) release from vesicles.
4. 4: NT Binds to receptor.
5. 5: Response occurs in post-synaptic cell.
6. 6: Some NT is broken down by enzymes in synaptic cleft.
7. 7: Some NT is taken up by pre-synaptic neuron and recycled.
8. 8: Some NT diffuses away from synapse.

Question 2

Define these theories for Pain Perception:

1. Specificity Theory
2. Pattern Theory
3. Gate and Neuromatrix Theories

Answer 2

1. Specificity Theory: something hurts, and you react to it.
2. Pattern Theory: signals integrated in spinal cord, and you react to it.
3. Body and mind continually interact, modulating the experience of pain.

Question 3

What is Phantom Pain?

• What are the two components of phantom pain?

Answer 3

Phantom Pain is the experince of pain in a missing limb, has long been a mystery.

It appears to have a 1.) physical component (irritation of nerves near site of amputation) and a 2.) psychological component (confusion and anxiety about the missing limb).

Question 4

Define Pain

Answer 4

Pain is considered to be a perception, not simply a sensation, because it is influenced by one’s psychological state.

• Pain is subjective - experienced differently by each individual
• Various neural mechanisms alter the intensity of pain

Question 5

Define Nociception

Answer 5

Nociception refers to traffic along nociceptive neural pathways, often triggering reflex avoidance responses, but not always.

• Nociceptive Receptors are activated by noxious stimuli (e.g. sharp poking, acid, extreme heat or cold), and sends signals that the brain is likely to interpret as pain.

Question 6

In the image below, where is pain perceived?

Where does nociception play a role in the pain pathway?

Answer 6

Pain is perceived consciously in the cerebral cortex.

Nociception occurs where nociceptive receptors are initially activated at the 1) primary afferent receptors, which causes neural information to travel along nociceptive pathways to 2) increase alertness.

Question 7

Sensing Pain

• Pain is the a)_____________ that people seek b)________. However, pain is c) __________, making both definition and treatment of pain difficult.
  
  1. In most cases, the sensation of pain is d) _______, in that it warns the brain about some type of injury or illness.
  2. Pain accounts for:
     
     • 20% of outpatient visits
     • 12% of prescriptions
     • $600 billion in health care spending per year.
  3. Pain tends to e)____________ if the symptoms are not controlled. Consequently, it is helpful to give people pain killers before surgery.
  4. The search for f)____ and g)_____ strategies to treat pain is urgent, as h)________ to prescription painkillers and other opioids is a growing crisis in the US.
  5. Chronic pain can be particularly debilitating:
     
     • Chronic pain persists i)________, often in the absence of obvious j) ________. Patients have difficulty getting respectful medical care.
     • Common causes: arthritis and other musculoskeletal disorders, autoimmune disease, chronic gastrointestinal diseases.
     • It is generally thought to be k)______ – the problem is with abnormal l) _________.
     • About 50 million Americans suffer from chronic pain.

Answer 7

Sensing Pain

• Pain is the most common reason that people seek medical care. However, pain is highly subjective, making both definition and treatment of pain difficult.
  
  1. In most cases, the sensation of pain is beneficial, in that it warns the brain about some type of injury or illness.
  2. Pain accounts for:
     
     • 20% of outpatient visits
     • 12% of prescriptions
     • $600 billion in health care spending per year.
  3. Pain tends to become worse over time if the symptoms are not controlled. Consequently, it is helpful to give people pain killers before surgery.
  4. The search for safe and effective strategies to treat pain is urgent, as addiction to prescription painkillers and other opioids is a growing crisis in the US.
  5. Chronic pain can be particularly debilitating:
     
     • Chronic pain persists for months or longer, often in the absence of obvious injury or disease. Patients have difficulty getting respectful medical care.
     • Common causes: arthritis and other musculoskeletal disorders, autoimmune disease, chronic gastrointestinal diseases.
     • It is generally thought to be neuropathic – the problem is with abnormal neural signaling.
     • About 50 million Americans suffer from chronic pain.

Question 8

Sensing Pain - Part 2

Pain is not always caused by a)_________ in some part of the body. In some cases it emerges elsewhere along the pain pathway.

1. b) ___________ – result of noxious stimulus arising in the periphery (eg: stepping on glass).
2. c) _________ – sprained ankle, arthritis – dull achy feeling.
3. d) ________ – originates in the nerve. Eg: diabetic neuropathy, shingles.
4. e) __________ – No identifiable lesion, yet pain persists.

There are two types of f) _________ , carried by different types of fibers:

1. g) _________ (primarily nociceptive pain)
   
   • prickling, stabbing sensation, good localization.
   • triggers nociceptive reflexes.
   • carried by myelinated nerve fibers, specifically Aδ (delta), and maybe Aβ (beta) fibers, which carry signals at about 5-30 m/sec.
2. h) ________ (impt in inflammatory pain)
   
   • burning, aching sensation
   • carried by unmyelinated nerve fibers (C fibers), at about 0.5–2 m/sec
   • poor localization

Answer 8

Sensing Pain - Part 2

Pain is not always caused by tissue damage in some part of the body. In some cases it emerges elsewhere along the pain pathway.

1. Nociceptive pain – result of noxious stimulus arising in the periphery (eg: stepping on glass).
2. Inflammatory pain – sprained ankle, arthritis – dull achy feeling.
3. Nerve pain – originates in the nerve. Eg: diabetic neuropathy, shingles.
4. Non-inflammatory, non-nerve pain. No identifiable lesion, yet pain persists.

There are two types of peripheral pain, carried by different types of fibers:

1. fast pain (primarily nociceptive pain)
   
   • prickling, stabbing sensation, good localization.
   • triggers nociceptive reflexes.
   • carried by myelinated nerve fibers, specifically Aδ (delta), and maybe Aβ (beta) fibers, which carry signals at about 5-30 m/sec.
2. slow pain (impt in inflammatory pain)
   
   • burning, aching sensation
   • carried by unmyelinated nerve fibers (C fibers), at about 0.5–2 m/sec
   • poor localization

Question 9

Example of Nociceptive Pain: Identify the structures that involve during a WITHDRAWAL REFLEX:

Answer 9

a) Direction of impulse
b) Dendrite of afferent neuron
c) Cell body of afferent neuron
d) Axon of afferent neuron
e) Cell body of interneuron
f) SPINAL CORD
g) Cell body of efferent neuron
h) Axon of efferent neuron
i) Muscle contracts and withdraws part being stimulated

Question 10

What affects YOUR perception of pain?

Answer 10

The sensation of pain is processed in the emotional and cognitive regions of the brain.

Feedback loops between pain, emotions and cognition -

• Pain can have a negative effect on emotions and on cognitive function. Conversely, a negative emotional state can lead to increased pain, whereas a positive state can reduce pain. Similarly, cognitive states such as attention and memory can either increase or decrease pain. Of course, emotions and cognition can also reciprocally interact. The minus sign refers to a negative effect and the plus sign refers to a positive effect.

This is from:

Nat Rev Neurosci. 2013 Jul; 14(7): 502–511.

Published online 2013 May 30. doi: 10.1038/nrn3516

Question 11

What are inflammatory mediators? Name some examples of these mediators.

Answer 11

Inflammatory mediators are substance released by damaged cells in the C-Fibers that directly stimulate nociceptors or sensitize them to make them more responsive to other stimuli.

Examples:

• Bradykinin
• K+
• acetylcholine - strong stimulant of nociceptors, and is released from certain cells when damaged

Question 12

What peptides are released by C Fibers and what do they do?

Answer 12

1. Substance P:
2. CGRP: aka calcitonin gene related protein, which is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain.

These peptides stimulate nociceptors on the C Fibers and also promote local inflmmation.

Question 13

1) What is the Gated Theory of Pain?
2) What was developed from the understanding of the Gated Theory of Pain?

Answer 13

The idea that rubbing the skin can help relieve deep pain, and also why liniments like Bengay work, and why anesthetic acupuncture (not traditional acupuncture) works.

HOW: synaptic transmission in pain pathways is “gated” by other afferent input. Stimulation of tactile afferents can, VIA INHIBITORY NEURONS, block pain transmission.

2) TENS Transcutaneous Electric Nerve Stimulation.

Question 14

Endogenous Opioids (endorphins) and Endogenous cannabanoids (endocannabanoids) are natural endogenous forms that Modify Pain Perception.

1. Define Endorphins and Endocannabanoids

Answer 14

1) Endogenous Opioids (endorphins) and Endogenous Endocannabanoids (endocannabanoids) are the body’s natural pain control mechanisms that can reduce pain without the use of drugs.

Question 15

Endogenous Opioids (endorphins) and Endogenous cannabanoids (endocannabanoids) are natural endogenous forms that Modify Pain Perception.

1. Define Endorphins and Endocannabanoids
2. What drugs affect this system?

BONUS QUESTION: What drug prevents the breakdown of endocannabanoids?

Answer 15

1) Endogenous Opioids (endorphins) and Endogenous Endocannabanoids (endocannabanoids) are the body’s natural pain control mechanisms that can reduce pain without the use of drugs.

2)

• a) Drugs that affect endorphins:
  
  • Morphine
  • Heroin
  • Oxycontin
  • Fentanyl
• b) Drugs that affect endocannabanoids:
  
  • Derivatives of marijuana
  • Non-steroidal anti-inflammatory drugs (NSAIDs) - these inhibit the break down of endocannabanoids

Question 16

What are the effects of opioids?

In the image below, where does endogenous or drug opioids come in to affect the level of pain perceived?

Answer 16

Opioids, endogenous or in drug form, reduce the release of the NT Substance P along the pain pathway => REDUCES PAIN

Release of Opiate NT or binding of exogenous morphine to the opiate receptor prevents the release of substance P at the synaptic cleft of the neuron of interest.

Question 17

What triggers endorphin release, and what is the release of endorphines closely associated with?

Answer 17

Endorphine release is triggered by pain and stress, which is thought to contribute to the runner’s high. This explains how people can endure extreme pain in a stressful situation.

Question 18

How do NSAIDs affect endocannabinoids?

Answer 18

Because of NSAIDs, endocannabinoids are active longer, which reduce pain neurotransmission.

Question 19

CB1 and CB2 are endocannabinoid receptors.

1. Where are these located?
2. How do these receptors on their respective location play a role in pain perception?

Answer 19

1. CB1s are found on Neurons; CB2s are found on Immune Cells.
2. • A) CB1s on neurons:
     
     • inhibit signaling along pain pathways
     • reduced pain perception
     • reduced anxiety/depression
   • B) CB2s on Immune Cells:
     
     • reduces inflammation

Question 20

Pharmaceutical Control of Pain:

1. Anti-inflammatory drugs a) _______ the b) ______ of nociceptors
2. Local anesthetics, such as lidocaine c) ____ pain by blocking the opening of d) ______ channels, thereby preventing e) ________.
3. Opioids and cannabinoids act at f) ______ levels to inhibit pain neurotransmission.

Answer 20

Pharmaceutical Control of Pain

1. Anti-inflammatory drugs a) reduce the b) stimulation of nociceptors.
2. Local anesthetics, such as lidocaine c) inhibit pain by blocking the opening of d) voltage-gated sodium channels, thereby preventing e) action potential firing.
3. Opioids and cannabinoids act at f) multiple levels to inhibit pain neurotransmission.

IMAGE: Opioids and cannabinoids act at multiple levels to inhibit pain neurotransmission by affecting:

• Perception (brain-level)
• Modulation (spinal level)
• Transmission (neuron pathway level)
• Transduction (stimuli site level)

Question 21

Define the Current Model of Placebo Effect

Answer 21

SEE IMAGE BELOW - The expectation of benefit associated with a placebo causes measurable changes in neurobiological signaling pathways, resulting in pain relief.

With placebos, there is a change in expectation of benefits in the patient, which impacts neurobiological signaling by changing the release of endorphins or dopamine or endogenous cannabinoids. In effect, this leads to pain relief.

Question 22

1. What type of conditions is the placebo effect found to be greatest?
   
   • a) Give some conditions of where placebos can sometimes work.
   • b) Give some conditions of where placebos are less likely to work.

Answer 22

1. The placebo effect is greatest on conditions that respond to the body’s own biochemicals, such as endogenous opioids and dopamine.
   
   • a) Placebos can sometimes work for:
     
     • Pain, depression, Parkinson’s Disease, Hypertension, Rhematoid arthritis (RA), Ulcers
   • b) Placebos are less likely to work for:
     
     • Atherosclerosis, cancer, growth-hormone deficiency, high cholesterol, infertility, obsessive-compulsive disorder

Question 23

Define the Nocebo Effect

What are some examples of Nocebo Effect?

Answer 23

Nocebo Effect is when negative expectations of the patient regarding a treatment cause the treatment* to have a *more negative effect than it otherwise would have.

Examples of Nocebo Effect relating to: (Image below)

1. Conditioning -
2. Instructural Learning -
3. Observational Learning -

Question 24

1. Knowing that a pain reliever has been given leads to a) ____ and b) ______ pain relief.
2. Pain returned c) _______ _______ when they were told that the infusion of d) ______ had stopped , than when it was stopped without their e) ________.

Answer 24

1. Knowing that a pain reliever has been given leads to a) faster and b) more effective pain relief
2. Pain returned more quickly when they were told that the infusion of d) morphine had stopped, than when it was stopped without their e) knowledge.