Pain Pathway

How does pain fit into the somatosenses?

1. Pain is a part of the somatosensory due to the fact that it refers to sensations felt in the skin such as itch, pain, or vibrations

2. Pain is a sensory and affective experience

What is the difference between chronic and acute pain?

Chronic pain refers to constant pain for an extended period of time

Acute pain refers to necessary pain for survival

What are the two types of chronic pain?

Neuropathic pain → pain due to injury to neurons in the pain pathway

Inflammatory pain → pain due to tissue damage leading to abnormal activity in the pain system

What are three abnormal changes in sensation associated with chronic pain?

1. Hyperalgesia → increased intensity of painful stimuli

2. Allodynia → when a normal non-painful stimuli becomes painful

3. Spontaneous pain → referring to sudden pain w/o stimulation

What other factors can influence our perception of pain?

1. Stress

2. Focusing on the pain

3. Mood

4. Genetics

5. Arousal state

6. Drugs

7. Disease/illness

Describe the ascending pain pathway

1. Input from tissue received from the primary somatosensory neuron

2. The first synapse at the dorsal horn of the spinal cord & immediately crosses the midline

3. The input from the spinal cord travels up via two tracts (bring input from SC to the brain :

   1. Spinothalamic tract

   2. Spinoreticulothalamic tract

4. The second synapse occurs either:

   1. thalamus - acts as a relay center for pain input before cortex

   2. parabrachial complex →integrates sensory input to the amygdala

5. The final synapse occurs at the cortex involving two systems

   1. Medial system → Synapse at the medial thalamus (Anterior cingulate cortex and insular cortex)

   2. Lateral system → Synapse at the lateral thalamus (somatosensory cortex)

Describe the neurons that are considered nociceptors on the primary somatosensory neuron

1. A-delta fibers → can be either nociceptive or non-nociceptive (medium mylinated)

2. C-fibers → always nociceptive (small and non-mylinated)

3. A-beta fibers → non-nociceptive (large and mylinated)

In the ascending pain pathway what are the two tracts carrying input from the spinal cord to other areas of the brain?

1. Spinothalamic tract → Input from Spinal cord to thalamus

2. Spinoreticulothalamic tract → Input from spinal cord to rostral ventromedial medulla or Input from SC to periaqueductal grey (thalamus) or Input from spinal cord to parabrachial nucleus (amygdala)

In the cortex of the ascending pain pathway there are two systems that are necessary for pain integration: Describe them?

1. Medial system → Involving the medial thalamus (includes the anterior cingulate cortex & insular cortex): system involved in linking sensory input with emotion

2. Lateral system → Involving the lateral thalamus (includes somatosensory cortex): system involved in localizing sensory input

Describe the descending pain pathway

1. Higher corties send sensory input to two main structures in the midbrain:

   1. Locus Coeruleus → Sends signals to SC to inhibit pain signals and rostral ventromedial medulla

   2. Periaqueductal Grey → Sends signals about fight or flight to rostral ventromedial medulla

2. All signals from LC and PG are recieved at the raphe magnus in the rostral ventromedial medulla

3. Signals are picked up by the two types of neurons found in the RVM which modulate pain signals

   1. On and off neurons

What are the two types of neurons in the rostral ventromedial medulla that modulate pain?

1. On neurons → increase pain signals when active

2. Off neurons → decrease pain signals when active

What are the functions of the two structures in the descending pain pathway that recieve input from higher sites?

1. Locus coeruleus helps to fine tune sensory input and sends signals to inhibit noceciptive pain

2. Periqueductal grey helps integrate input from cortex, amygdala and hypothalamus to iduce F and F responses

What nucleus is found in the rostral ventromedial meduall? What is the function?

Raphe magnus → control center for descending modulation to spinal cord

How can we stop pain from getting to the CNS?

1. Block the excitation of nociceptors

2. Block channels involved with the excitation of nociceptors

   1. Nav1.7

   2. TRPV1

3. Use opioids

4. Block NMDA receptors

5. Use cannaboids

Explain the how blocking the Nav1.7 and TRPV1 channels help to modulate pain?

1. Blocking the Nav1.7 channel on C and Adelta fibers blocks the influx of sodium → leading to less pain signals

   1. We know this because people with too many Nac1.7 channels feel too much pain

2. Blocking the TRPV1 channels in the C and Adelta fibers blocks the influx of both Na and Ca into neurons → leading to less pain

   1. We know this because this channel is involved in snesing heat, acid, and capsacin

What two medications are currently in the market that are associated with the Nav1.7 and TRPV1 channels for pain?

1. Topical Anesthetics (Lidoocaine)

   1. Non-selectively binds to Nav1.7 channel

2. Topical Capsacinoids (capsaicin cream)

   1. A TPRV1 agonist

   2. Too much of it causes desensitization → neurons stop firing to pain signals

Explain how are opioids involved in modulating pain?

Opioids can bind to mu receptors found all throughout the pain system thus inhibiting pain at the primary afferent input, dorsal horn neurons, and ascending pain sites and activating inhibitory sites in the descending pathway

What are the two structures that are more impacted by opioids (morphone) considering they have a lot of mu receptors?

PAG and RVM therefore descending pathway is more impacted by opioids in reducing pain signals

Explain how opioid agonist reduce pain in the descending pathway?

1. Opioids can directly inhibit firing of on-cells in the RVM

2. Opioids can indirectly excite firing of off-cells in the RVM by binding to local GABA neurons

   1. Removing GABA inhibition on off-cells ensures that off-cells are activate

Explain how cannabinoids modulate pain

1. Cannabinoid receptors CB1 and CB2 are found all throughout the pain system and when cannabinoids bind to them they can inhibit pain signal:

   1. Inhibit it at the primary afferent neuron

   2. inhibit the dorsal horn neurons

   3. inhibit ascending sites

   4. Indirectly activate the descending inhibitory sites (PG and RVM)

Explain how the NMDA receptor antagonist can be involved in modulating pain

NMDA receptors are involved in dissociative pain (understanding there is pain but not caring about it)

• Blocking NMDA receptors blocks the relay pain input from the thalamus to the cortex (Brain never receives pain signals)

• Blocking NMDA receptor can block excitation of spinal cord neurons so no pain input from the brain gets sent to SC

How do anti-depressant drugs help modulate pain in the spinal cord? What are examples of these drugs and how they work?

Anti-depressant drugs help to reduce pain by delaying it and acting directly on the pain pathway

1. TCA (Tricyclic anti-depressant) and SNRIs (Serotonin Noradrenaline) both block serotonin and Noradrengic reuptake at the spinal cord allowing for long exposure of 5-HT and NA → helps reduce pain signals

Why do anti-depressants inhibit the reuptake of 5-HT and NA at the spinal cord?

Because both the RVM and LC send fibers to the SC to inhibit pain

1. RVM sends 5-HT fibers to release 5-HT

2. LC sends noradegeneric fibers to release NA

Explain how ani-inflammatory drugs can help to modulate pain and provide an example

Anti-inflammatory drugs (NSAIDS) help stop inflammatory pain by blocking COX

Examples: Aspirin and Ibuprofen