Comprehensive Notes on Pain and Pain Suppression

Two types of axons in nociceptors:
- Highly myelinated (A delta fibers)
- Unmyelinated (C fibers)
Myelin's role is to insulate neurons to increase signal speed due to gaps in myelin; it does not protect against damage.
Evolutionary purpose of slower C fibers:
- A delta fibers: Immediate, sharp pain localization.
- C fibers: Dull, general pain to protect the injured area.

Nociceptors (red neurons) have cell bodies in the dorsal root ganglion and synapse in the dorsal root of the spinal cord.
Axons cross the midline and ascend to the thalamus via the spinal thalamic tract.
Pain and temperature information follows this tract.
Substance P, in addition to glutamate, is released at the synapse between nociceptors and spinal cord neurons.

Pain signals from the thalamus stimulate thalamic neurons, which synapse on primary somatosensory cortex neurons.
The primary somatosensory cortex maps the body surface via a homunculus.
Representation size is proportional to the number of sensory receptors.
Awareness of pain and its location occurs when the signal reaches the primary somatosensory cortex.
Pain perception is in the brain.
Phantom pains: Experiencing pain in an amputated body part.
- The cortical representation of the missing limb is still present and can fire action potentials.

Physical sensation: The location and intensity of pain mapped by the somatosensory cortex.
Emotional component: Unpleasantness processed in the anterior cingulate cortex.
Both components are needed for comprehensive pain experience.

Experiment: Inducing pain by immersing hands in 47°C water during brain scans.
- Increased activity in primary somatosensory cortex and anterior cingulate cortex.
Hypnotically induced pain reduction:
- No difference in primary somatosensory cortex activity.
- Lower activity in anterior cingulate cortex.
Conclusion:
- Anterior cingulate cortex: Responsible for the unpleasantness of pain.
- Somatosensory cortex: Responsible for the presence and location of pain.

Hypnosis: Reduces activity in the anterior cingulate cortex.
Non-drug approaches:
- Descending analgesia circuit.
- Capsaicin, NSAIDs, paracetamol, opiates, and cannabis affect pain.

Inhibits pain signal entry into the central nervous system at the first synapse.
Located in the brainstem, starting from the periaqueductal gray (PAG).
The PAG activates the Raphé Magnus, which activates inhibitory interneurons in the spinal cord and dorsal horn.
This circuit inhibits both the spinal cord neuron and the presynaptic terminal from the nociceptor.
The circuit stops the release of glutamate or substance P, or prevents the receiving neuron from firing action potentials.
Activation:
- Artificially: Stimulating electrodes implanted in the periaqueductal gray.
- Naturally: Stressful or extreme situations.
Adrenaline does not suppress pain directly; it's a consequence of the stress response.

Non-active substance reduces pain when the person believes it will.
Skin cream study: Activation in the dorsolateral prefrontal cortex and periaqueductal gray.

Blocks opiate receptors, negating pain reduction from the placebo effect, acupuncture, and stressful situations.
Hypnosis works on anterior cingulate cortex and would not be affected by naloxone.

Hot substance in chili peppers used in topical creams like deep heat.
Effective for dull, C fiber pain in muscles.
Triggers pain response in C fibers, causing them to release substance P until depleted.
Brief overstimulation leads to a period of reduced pain as substance P is replenished.

Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase (Cox 1 and Cox 2) enzymes.
Act in the periphery and do not cross the blood-brain barrier well.
Reduce production of prostaglandins, which are involved in inflammation and sensitization of free nerve endings.
Cox 1 is involved in blood clotting and stomach lining protection. Reduces blood clotting capacity.
Inhibiting Cox 1 can lead to stomach ulcers.
Efforts to develop Cox 2- specific inhibitors have had limited success due to side effects.

Not an NSAID and does not block Cox 1 or Cox 2.
Hypothesis: Agonist of CB1 receptors.
Paracetamol is converted into AM404 in the body.
AM404 binds to cannabinoid receptors (CB1 receptors).
If CB1 receptors are blocked with an antagonist, paracetamol's pain-reducing properties are negated.
Toxic to the liver in high doses.

Derived from the opium poppy or synthetically produced.
Used for pain relief for thousands of years.
Well known for abuse potential.
Morphine is used clinically, especially for severe pain.
Codeine is found in some cough medicines and has pain-reducing capacities.
Heroin (Diamorphine) crosses the blood-brain barrier more easily than morphine.
Oxycodone is available in pill form.
Fentanyl is very addictive and has a long half-life.
Relieves cough, relieves diarrhea, reduces body temperature, induces sleep, and generally makes people feel good.

Mimic endogenous opioids and bind to opioid receptors.
Three subtypes of opioid receptors: delta, kappa, and mu.
Located throughout the brain:
- Hypothalamus: Controls body temperature.
- Reticular formation: Involved in falling asleep.
- VTA and nucleus accumbens: Involved in addiction.
- Periaqueductal gray: Descending analgesic circuit.
- Brainstem: Controls breathing.
In the gut: Reduce diarrhea.
Activate and mimic the descending analgesic circuit activity by inhibiting inhibitory interneurons in the periaqueductal gray and suppressing pain signals.