Pain and Pain Suppression Flashcards
Highly myelinated axons
Convey mechanical pain very quickly and precisely, very informative about location
Unmyelinated axons
Convey different kinds of pain more slowly and less precisely, more vague about location
Types of nociceptors
Sensitive to extremes of mechanical stimulation
Sensitive to pungent irritants (eg mustard oil)
Sensitive to extremes of temperature, acid and capsaicin
Pain Perception
Can be independent of input
Physical pain perception –> Primary SS Cortex
Unpleasantness perception –> Anterior Cingulate Cortex
The Descending Analgesia Circuit reduces pain by…
Inhibiting the pain signal from entering the central nervous system at the first synapse
How could pain be suppressed? (Non-drug)
- Direct stimulation of the PAG (Periacridotal Grey Area) by electrodes - chronic pain sufferers
- Stressful situations - athletes and soldiers
- Placebo effect
- Acupuncture (tested using naloxone, an opiate receptor blocker)
What is Capsaicin?
Used topically on the skin for muscle pain and feels hot.
How does capsaicin work?
Depletes sensory neuron terminals of substance P, providing local analgesia
How do Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) - eg aspirin, ibuprofen and COX-2 inhibitors - work?
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
Side effects of inhibiting COX-1
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
How does paracetamol work?
Still under investigation but:
1. Paracetamol reacts with endogenous molecules to form AM404, an agonist of the TRPV1 and CB-1 cannabinoid receptors
Where are TRPV1 channels found?
On nociceptors
Where are CB-1 receptors found?
In many central and peripheral pain-related circuits, including Descending Analgesia Circuit where they reduce inhibition
Opiates
Derived from the opium poppy
Long-time used and very powerful analgesics
Well-known for their abuse potential
Different forms of opiates
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
Half-life of opiates
Around 3-4 hours
Opiates short term effects
Relieve pain Relieve cough Relieve diarrhoea Induce hypothermia Induce sleep Stimulate pleasure
Physiological action of opiates
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
Who discovered opioid receptors
Discovered in 1973 by Pert and Snyder
Where are opioid receptors found?
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)
Opiates long term effects
Constipation Pupil constriction Menstrual irregularity Reduced libido But heavy withdrawal symptoms
Heroin Withdrawal Effects
Begin 6-12 hours after last dose and disappear in a week
- Restlessness
- Watering eyes
- Chills, shivering
- Nausea, vomiting
- Tremor
- Runny nose
- Sweating
- Gooseflesh
- Diarrhoea
- Muscle spasms
Countering withdrawal effects
More heroin
Methadone
Acupuncture (or modern equivalent)
Avoiding drug-related contexts
Addictiveness in the Ventral Tegmental Area (VTA)
Opiates inhibit GABA-ergic interneurons
This releases inhibition from neurones which project to Nucleus Accumbens
Triggers more dopamine release
How does cannabis work?
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)
Recreational short term effects
- Reduction in anxiety
- Dissociation of ideas
- Heightened sensation
- Distorted sense of time (seems slower)
- Intense emotional experiences
- Hallucinations (infrequent)
Medical cannabis short term effects
Reduces nausea Increase in appetite Dilation of bronchioles Blocks seizures Decreases severity of glaucoma
Reducing pain by using cannabis
Cannabis is as effective as opiates for acute pain
Greater potency and efficacy than opiates from chronic pain (but side effects)
What sites help reduce pain by using cannabis
- Peripheral nerves
- Direct spinal cord activity
- Descending analgesia circuit
- Anterior Cingulate Cortex
Cannabis intoxication
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
Cannabis intoxication
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
Cannabis physiological action
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
Function of Endocannabinoids
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)
Where are cannabinoid receptors?
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)
Woman feeling no pain case study
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)
Cannabis long term effects
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)
Physical dependence of cannabis
Tolerance develops during extended use, but withdrawal symptoms are rare
Long term users may experience sensitisation of the desired effects
Psychological dependence of cannabis
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
