Pain and Pain Suppression

Question 1

Highly myelinated axons

Answer 1

Convey mechanical pain very quickly and precisely, very informative about location

Question 2

Unmyelinated axons

Answer 2

Convey different kinds of pain more slowly and less precisely, more vague about location

Question 3

Types of nociceptors

Answer 3

Sensitive to extremes of mechanical stimulation
Sensitive to pungent irritants (eg mustard oil)
Sensitive to extremes of temperature, acid and capsaicin

Question 4

Pain Perception

Answer 4

Can be independent of input

Physical pain perception –> Primary SS Cortex
Unpleasantness perception –> Anterior Cingulate Cortex

Question 5

The Descending Analgesia Circuit reduces pain by…

Answer 5

Inhibiting the pain signal from entering the central nervous system at the first synapse

Question 6

How could pain be suppressed? (Non-drug)

Answer 6

1. Direct stimulation of the PAG (Periacridotal Grey Area) by electrodes - chronic pain sufferers
2. Stressful situations - athletes and soldiers
3. Placebo effect
4. Acupuncture (tested using naloxone, an opiate receptor blocker)

Question 7

What is Capsaicin?

Answer 7

Used topically on the skin for muscle pain and feels hot.

Question 8

How does capsaicin work?

Answer 8

Depletes sensory neuron terminals of substance P, providing local analgesia

Question 9

How do Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) - eg aspirin, ibuprofen and COX-2 inhibitors - work?

Answer 9

Act peripherally - poor blood-brain-barrier penetration because of binding proteins in the blood
Inhibit Cyclo-Oxygenase 1 and 2 (COX-1 and COX-2) which reduce the production of prostaglandins

Question 10

Side effects of inhibiting COX-1

Answer 10

COX-1 is involved in blood clotting so taking aspirin prevents blood clotting
Also involved in protecting the stomach lining from acid - making NSAIDs bad for the stomach

Question 11

How does paracetamol work?

Answer 11

Still under investigation but:

1. Paracetamol reacts with endogenous molecules to form AM404, an agonist of the TRPV1 and CB-1 cannabinoid receptors

Question 12

Where are TRPV1 channels found?

Answer 12

On nociceptors

Question 13

Where are CB-1 receptors found?

Answer 13

In many central and peripheral pain-related circuits, including Descending Analgesia Circuit where they reduce inhibition

Question 14

Opiates

Answer 14

Derived from the opium poppy
Long-time used and very powerful analgesics
Well-known for their abuse potential

Question 15

Different forms of opiates

Answer 15

Opium - mostly smoked or eaten
Morphine - many different ways, only 20% crosses blood-brain barrier
Codeine - typically oral, as cough suppressant
Heroin - typically injected; lipid soluble so more crosses the blood-brain barrier
Oxycodone - pills with either fast (15 minutes on empty stomach) or slow uptake

Question 16

Half-life of opiates

Answer 16

Around 3-4 hours

Question 17

Opiates short term effects

Answer 17

Relieve pain
Relieve cough
Relieve diarrhoea
Induce hypothermia
Induce sleep
Stimulate pleasure

Question 18

Physiological action of opiates

Answer 18

Opiate drugs mimic the action of endogenous opioids: endorphins
They bind the endogenous opioid receptors, which can be found in many places in the body and brain

Question 19

Who discovered opioid receptors

Answer 19

Discovered in 1973 by Pert and Snyder

Question 20

Where are opioid receptors found?

Answer 20

Preoptic area (hypothermia)
Mesencephalic Reticular Formation (sedation)
Locus Coeruleus (sedation)
Ventral Tegmental Area and Nucleus Accumbens (rewarding)
Peri-Aqueductal Grey Area (pain relief, pleasure)
Brainstem (coughing centre, breathing regulation)
In the periphery (diarrhoea relief)

Question 21

Opiates long term effects

Answer 21

Constipation
Pupil constriction
Menstrual irregularity
Reduced libido
But heavy withdrawal symptoms

Question 22

Heroin Withdrawal Effects

Answer 22

Begin 6-12 hours after last dose and disappear in a week

1. Restlessness
2. Watering eyes
3. Chills, shivering
4. Nausea, vomiting
5. Tremor
6. Runny nose
7. Sweating
8. Gooseflesh
9. Diarrhoea
10. Muscle spasms

Question 23

Countering withdrawal effects

Answer 23

More heroin
Methadone
Acupuncture (or modern equivalent)
Avoiding drug-related contexts

Question 24

Addictiveness in the Ventral Tegmental Area (VTA)

Answer 24

Opiates inhibit GABA-ergic interneurons
This releases inhibition from neurones which project to Nucleus Accumbens
Triggers more dopamine release

Question 25

How does cannabis work?

Answer 25

20-50% of active compound THC is taken up from smoke, less from ingested (6%) THC is very lipid soluble and easily crosses the blood-brain barrier It is easily stored in fat tissue, and has a half-life of 7 days (still detectable after 30 days)

Question 26

Recreational short term effects

Answer 26

1. Reduction in anxiety 2. Dissociation of ideas 3. Heightened sensation 4. Distorted sense of time (seems slower) 5. Intense emotional experiences 6. Hallucinations (infrequent)

Question 27

Medical cannabis short term effects

Answer 27

``` Reduces nausea Increase in appetite Dilation of bronchioles Blocks seizures Decreases severity of glaucoma ```

Question 28

Reducing pain by using cannabis

Answer 28

Cannabis is as effective as opiates for acute pain | Greater potency and efficacy than opiates from chronic pain (but side effects)

Question 29

What sites help reduce pain by using cannabis

Answer 29

1. Peripheral nerves 2. Direct spinal cord activity 3. Descending analgesia circuit 4. Anterior Cingulate Cortex

Question 30

Cannabis intoxication

Answer 30

Intoxication similar to alcohol and causes uncoordinated motor performance and slower reflexes even a day later Also causes attention and short-term memory problems as well as panic attacks and paranoia

Question 30

Cannabis intoxication

Answer 30

Intoxication similar to alcohol and causes uncoordinated motor performance and slower reflexes even a day later Also causes attention and short-term memory problems as well as panic attacks and paranoia

Question 31

Cannabis physiological action

Answer 31

Active ingredient is THC which binds to cannainoid receptors in the brain. Endogenous ligands are anandamide and 2-AG The highest concentration of cannabinoid receptors exists in the hippocampus

Question 32

Function of Endocannabinoids

Answer 32

Released from post-synaptic side of a stimulated synapse Work in the close vicinity on the other synapses Suppresses the pre-synaptic release of neurotransmitters In the hippocampus, this affects GABA, hence suppressing inhibition: depolarisation-induced Suppression of Inhibition (DSI)

Question 33

Where are cannabinoid receptors?

Answer 33

Cerebral cortex (psycho-active effects) Hippocampus (memory effects) Movement control centres (motor dysfunction) Brain stem (analgesia, vomiting control, sleep) Spinal cord (analgesia) Hypothalamus (appetite, sleep) Amygdala (emotions)

Question 34

Woman feeling no pain case study

Answer 34

She repetitively burnt herself on her stove without noticing and didn't need any post-surgical pain relief. They found a defect in the FAAH enzyme that breaks down anandamide. She therefore had very high levels of anandamide (but not 2-AG as that isn't broken down by FAAH)

Question 35

Cannabis long term effects

Answer 35

Problems associated with smoking (not related to THC) Impairments in memory recall Impairments in attention Slower decision making Decline in IQ with persistent use (from age 13-38) Especially vulnerable if starting during adolescence Increased odds of psychosis by up to 5x with high potency versions (skunk)

Question 36

Physical dependence of cannabis

Answer 36

Tolerance develops during extended use, but withdrawal symptoms are rare Long term users may experience sensitisation of the desired effects

Question 37

Psychological dependence of cannabis

Answer 37

THC acts directly on nucleus accumbens to increase dopamine release from VTA terminals Yet people typically smoked only occasionally and could drop habit fairly easily More recent versions like skunk have higher addiction levels